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PMID
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).
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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK fusion Advanced Solid Tumor predicted - sensitive Repotrectinib Phase I Actionable In a Phase I (TRIDENT-1) trial, Augtyro (repotrectinib) treatment resulted in stable disease in 25% (4/16) of patient with advanced solid tumor harboring ALK fusions who completed 2 cycles of treatment (J Clin Oncol 36, 2018 (suppl; abstr 2513); NCT03093116). detail...
ROS1 fusion Advanced Solid Tumor predicted - sensitive Repotrectinib Phase I Actionable In a Phase I (TRIDENT-1) trial, Augtyro (repotrectinib) treatment resulted in partial response in 21.6% (8/37) of patients with advanced solid tumors harboring ROS1 or NTRK fusions (J Clin Oncol 36, 2018 (suppl; abstr 2513); NCT03093116). detail...
ROS1 fusion ROS1 G2032R Advanced Solid Tumor predicted - sensitive Repotrectinib Phase I Actionable In a Phase I (TRIDENT-1) trial, Augtyro (repotrectinib) treatment resulted in partial response in a patient with advanced solid tumor harboring ROS1 G2032R in the context of ROS1 fusion (J Clin Oncol 36, 2018 (suppl; abstr 2513); NCT03093116). detail...