Reference Detail

Ref Type

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).

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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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...