P1.04 - Phase I dose escalation and expansion study to evaluate safety and efficacy of INC280 in patients with advanced MET-dependent solid tumors

Abstract

ABSTRACT Background: MET dysregulation occurs in multiple cancers, causing activation of the MET receptor tyrosine kinase. INC280 is an oral, highly selective MET inhibitor that has exhibited preclinical and preliminary clinical anti-tumor activity in various solid tumors. This dose escalation and expansion study was designed to evaluate INC280 safety and efficacy in patients (pts) with advanced MET-dependent solid tumors. Methods: The primary objectives of this Phase (Ph) I study were to determine the MTD or recommended Ph II dose (RP2D), and safety and tolerability of INC280. The secondary objectives were efficacy and PK assessment. Eligible pts (aged ≥18 years, PS ≤2) had tumors with high Met expression that were refractory to currently available therapies or for which no therapies existed. Results: As of Sep 28, 2014, 91 pts were enrolled (median age 57 years, 70% male, 56% PS 0, 47% Asian): 38 in the dose escalation part and 53 in the dose expansion part. Pts were treated in 7 dose cohorts of 100-600 mg BID capsules or 400 mg BID tablets. DLTs occurred at 200, 250, and 450 (1 pt each) mg BID capsules and were Grade 3 fatigue (2 pts) and Grade 3 blood bilirubin increase (1 pt). The most frequent drug-related AEs (any grade) were nausea (33%), fatigue (25%), and vomiting (24%). The most common Grade 3/4 drug-related AEs were fatigue (4%) and increased lipase levels (3%) and occurred at 200 (1 pt), 250 (2 pts), 450 (1pt) and 600 (3 pts) mg BID capsules. RP2D was established at 600 mg BID capsules, but film-coated 400 mg INC280 tablets were developed and tested to improve pt convenience and compliance. INC280 400 mg BID tablets had comparable tolerability, safety profile and exposure compared with 600 mg BID capsules. The mean (CV%) steady state AUClast (Tlast ∼ 8h) and Cmax after 400 mg BID tablet vs 600 mg BID capsule were 24654 (33%, N = 4) vs 21249 (60%, N = 23) h*ng/mL and 7425 (30%, N = 4) vs 5240 (67%, N = 23) ng/mL respectively. Clinical activity was observed in advanced NSCLC patients, and updated efficacy data will be presented. Conclusions: Orally administered INC280 was well tolerated with a manageable safety profile. MTD was not reached, but the RP2D was established at 600 mg BID for capsules and 400 mg BID for tablets. Clinical trial identifier: NCT01324479.