Background: Despite high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients (pts) with EGFR-mut NSCLC ultimately relapse. Dysregulation of the MET pathway is implicated as a therapeutically tractable resistance mechanism, occurring in 15–20% of cases. INC280 is a highly selective, oral MET inhibitor with preclinical activity in EGFR-mut/MET-activated NSCLC when combined with EGFR TKIs. Methods: This Ph Ib/II, open-label, dose-escalation study of INC280 plus gef was performed in pts (age ≥18 yrs, ECOG PS ≤2) with EGFR-mut NSCLC who progressed after prior EGFR TKI, and have confirmed MET dysregulation (amplification [FISH ≥5 CN] or overexpression [IHC 2/3+]). The primary objective (Ph Ib) was to determine the MTD/recommended Ph II dose (RP2D) of INC280 plus gef; secondary objectives were safety, efficacy, pharmacodynamics and PK. An adaptive Bayesian logistic regression model with overdose control guided dose escalation to establish the MTD. Results: As of December 2, 2013, 41 pts were enrolled in the ongoing Ph Ib part of the study (59% female, median age 58 years). Pts were treated with INC280 at 7 dose cohorts of 100–800 mg QD and 200–600 mg BID, in combination with gef 250 mg QD. Dose-limiting toxicities (DLTs) occurred in 2 pts: dizziness (800 mg QD) and dyspnea (600 mg BID). The most frequent drug-related AEs (any grade [Gr]) were nausea (27 %), vomiting, diarrhea, and rash (all 22%). The most common drug-related Gr 3/4 AEs were increased lipase (7 %), and increased amylase (5%). For one death, causality to INC280 was not ruled out. INC280 exposure increased with dose from 100–800 mg QD and 200–400 mg BID; preliminary data show no PK interactions with gef. Partial responses were seen in 6/41 (15%) evaluable pts; 5 confirmed, 1 unconfirmed, including 3/7 pts (43%) on 400 mg BID; 5/6 responders had EGFR TKIs as a last treatment prior to study entry. All responders had high MET status. Conclusions: Oral INC280 in combination with gef is well tolerated; the RP2D has not yet been defined. Preliminary clinical activity supports further evaluation of INC280 combined with gef in MET-positive NSCLC resistant to EGFR TKIs. Clinical trial identifier: NCT01610336. Clinical trial information: NCT01610336.