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Authors AE. Drilon, SI Ou, BC Cho, DW Kim, J Lee, JJ Lin, VW Zhu, HR Kim, TM Kim, MJ Ahn, DR Camidge, JKC Lim, S Stopatschinskaja, JJ Cui, DM Hyman, RC Doebele, AT Shaw
Title A phase 1 study of the next-generation ALK/ROS1/TRK inhibitor ropotrectinib (TPX-0005) in patients with advanced ALK/ROS1/NTRK+ cancers (TRIDENT-1).
Journal Vol Issue Date Pages Journal Short Title
J Clin Oncol 36 no. 16_suppl May 2018 J Clin Oncol
URL https://ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.2513
Abstract Text Background: Pts with ALK/ROS1/NTRK fusion-positive cancers can develop on-target TKI resistance [e.g. solvent front mutations (SFMs)] and/or central nervous system (CNS) relapse. Ropotrectinib is a potent next-generation ALK/ROS1/TRK TKI designed to inhibit SFMs in addition to most clinically relevant resistance mutations. Methods: Phase I eligible pts had ALK, ROS1, or NTRK1-3 fusion-positive advanced solid tumors and were TKI-naïve or TKI pre-treated. Pts with treated/untreated asymptomatic brain mets were allowed. Dose escalation followed a 3+3 design. Results: As of Jan 2, 2018, 65 pts (28 ALK+, 29 ROS1+, and 8 NTRK+) received at least 1 dose of ropotrectinib. The most common tumor was NSCLC (83%). The median # of prior chemo- or immune-therapy was 1 (range 0-9). Many pts were TKI pre-treated (86% of ALK+ had ≥ 2 prior TKIs, 66% of ROS1+ and 50% of NTRK+ had ≥ 1 prior TKIs). 23 pts (35%) had baseline CNS metastases, including 52% with untreated CNS disease. Pts were treated over 5 dose levels/schedules (40–240 mg QD & 160 mg BID). The majority of AEs were G1-2. Treatment-related AEs ( > 10% of pts) included: dysgeusia (38%), dizziness (35%), paresthesia (24%), nausea (12%), anemia, constipation, fatigue, and oral numbness (11% each). DLTs occurred in 2 NSCLC pts: G3 dizziness at 240 mg QD (resolved with dose reduction) and G3 dyspnea/hypoxia at 160 mg BID (resolved with drug discontinuation). The MTD has not been reached. Dose escalation is ongoing. Confirmed partial responses (cPR, RECISTv1.1, n = 8) were observed in TKI-naïve or TKI pre-treated ROS1+/NTRK+ pts at all dose levels. These include pts with acquired SFM+ tumors (1 entrectinib-refractory NTRK3 G623E+, 1 crizotinib-refractory ROS1 G2032R+ pt with untreated CNS mets). The median duration on study of cPRs was 6.7 mos (range 2.6-9.9+ mos), and 88% (7/8) of responses are ongoing. Of the 16 ALK+ pts completed 2 cycles of ropo, 4 had confirmed SD (4 cycles) as best response at data cutoff. Conclusions: Ropotrectinib was well-tolerated and exhibited both intra- and extra-cranial clinical activity in TKI-refractory ROS1+ and NTRK+ pts with SFM-containing tumors. Clinical trial information: NCT03093116.

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