444PD - Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1/TRK fusion-positive solid tumors (TRIDENT-1 study)

Repotrectinib is a next-generation ROS1/TRK/ALK TKI with >90-fold potency versus crizotinib against ROS1 and >100-fold potency versus larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. Preclinical studies demonstrate robust activity against all known ROS1/TRK resistance mutations, including the most common solvent-front mutations (SFM) ROS1 G2032R, TRKA G595R, and TRKC G623R/E. In the ongoing phase 1 study (NCT03093116), TKI-naïve and TKI-pretreated (≥1 TKI) pts with advanced ROS1, TRK, or ALK fusion+ solid tumors received repotrectinib. Endpoints include safety, PK, and confirmed overall response (cORR). As of 4-March-2019, 83 pts were treated with repotrectinib (dose levels from 40mg QD to 200mg BID under fasted/fed conditions). Most AEs were manageable and grade (gr) 1-2. The most common treatment-emergent AEs (found in>30% of pts) were dizziness (57%), dysgeusia (51%), dyspnea (30%), and fatigue (30%). Four DLTs occurred and were manageable with dose modifications: gr3 dyspnea/hypoxia (n=1); gr2 (n=1) and gr3 (n=1) dizziness at 160mg BID, and gr3 dizziness (n=1) at 240mg QD. In ROS1+ NSCLC, the median number of prior TKIs was 1 (0-3); all TKI-naïve and 77% of TKI-pretreated pts received prior chemotherapy. In 11 evaluable TKI-naïve ROS1+ NSCLC pts, cORR by Blinded Central Review (BCR) was 82% (95% CI 48 - 98); median duration of response was not reached ((range 5.6 - 17.7+ months (mos)). In 18 ROS1+ NSCLC pts pretreated with 1 prior TKI, cORR by BCR was 39% (95% CI 17 – 64), and in 11 pts with 1 prior TKI at doses of 160mg QD or above cORR was 55% (95% CI 23 - 83). All pts with ROS1 G2032R had tumor regression [cORR of 40% (n=2/5)]. In 1 TKI-pretreated pt with ETV6-NTRK3+ and an acquired TRKC G623E-mutant salivary gland tumor, a cPR of 9.8 mos was achieved; the patient was treated for 17.9 mos. Enrollment continues. Updated data in ∼10 additional ROS1+ NSCLC and TRK+ solid tumor pts will be presented. Repotrectinib was well tolerated and demonstrated encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors. NCT03093116. Turning Point Therapeutics Inc, San Diego, CA, USA. Turning Point Therapeutics Inc, San Diego, CA, USA. A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche; Honoraria (self), Advisory / Consultancy: Loxo Oncology/Bayer/Lilly; Honoraria (self), Advisory / Consultancy: TP Therapeutics Inc; Honoraria (self), Advisory / Consultancy: AstraZ