Alka-372-001: First-in-human, phase I study of entrectinib – an oral pan-trk, ROS1, and ALK inhibitor – in patients with advanced solid tumors with relevant molecular alterations.

2517 Background: Entrectinib (formerly RXDX-101) is a potent and selective oral small molecule inhibitor of the TrkA/B/C, ROS1, and ALK kinases. Schedule A (fasted, 4d on/3d off for 3wks, 1 wk rest) demonstrated significant antitumor activity (ASCO 2014). This abstract reports completion of Sch A and two other ongoing dosing schedules (B and C). Methods: Pts with advanced solid tumors with molecular alterations in TrkA, ROS1 or ALK were treated in Sch B (QD) or Sch C (4d on/3d off), both in fed state. Results: 31 pts were treated in Sch A (N=19), B (N=6), or C (N=6). In Sch A, doses > 800 mg/m2 did not increase exposure significantly. Thus, accrual in Sch A was closed. Various dose levels (mg/m2) were explored in Sch B [200 (n=3); 400 (n=3)] and Sch C [400 (n=3); 800 (n=3)]. 7 pts had objective responses: 6 PR, 1CR (see Table). We are the first to report clinical activity of a Trk inhibitor in a pt with NTRK1+ (encoding TrkA) CRC. Of 7 ROS1-rearranged evaluable/measurable NSCLC pts, 4 have had an objective response (ORR: 57%), with a median duration of 6+ months. Moreover, in ROS1 pts treated at ≥ 400 mg/m2, the ORR was 80% (4 of 5 pts). Entrectinib is well tolerated. The majority of pts reported G1/ G2 AEs. 13 pts reported ≥ G3 AEs. Asthenia and muscle weakness were possibly related ≥ grade 3 AEs (both reversible). No DLTs have been reported to date. In Sch A, entrectinib was readily absorbed and exposures increased dose-proportionally up to 800 mg/m2. In fed state, entrectinib exposures were approx. 2x compared to fasted state. Conclusions: In this trial with entrectinib administered in 3 different dosing schedules, significant antitumor response was observed in pts with relevant molecular alterations, notably ROS1-rearranged NSCLC at doses ≥ 400 mg/m2/day and the only NTRK1 rearranged pt treated to date. Accrual in Sch B and C continues until RP2D is achieved, followed by dedicated studies in selected tumor types. Clinical trial information: NCT02097810.Objective responses. Tumor type (alteration) Sch/Dose (mg/m2) Best Response Duration of Response (cycles) NSCLC (ALK) A/800 PR 10 NSCLC (ROS1) A/1200 PR 14+ C/400 PR 7+ C/400 CR 5+ B/400 PR 3+ CRC (NTRK1) A/1600 PR 3 Neuroblastoma (ALK) A/800 PR 9