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Ref Type Abstract
PMID
Authors B. Besse, A.E. Drilon, B.C. Cho, D.R. Camidge, J. Neal, C-C. Lin, S.V. Liu, M. Nagasaka, S.C-H. Kao, E. Felip, A.J. Van Der Wekken, C.C. Lin, J.R. Bauman, S. Gadgeel, M. Samant, J. Shen, Y. Sun, V.W. Zhu, V.A. Upadhyay, J.J. Lin
Title 1256MO Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 35 supplement 2 September 2024 S804-S805 Ann Oncol
URL https://www.annalsofoncology.org/article/S0923-7534(24)02832-1/fulltext
Abstract Text Background Zidesamtinib is a brain-penetrant, TRK-sparing, highly selective ROS1 tyrosine kinase inhibitor (TKI) with activity against diverse ROS1 fusions and resistance mutations including G2032R. Methods The global ARROS-1 phase (ph) 1 (NCT05118789) enrolled pts with heavily pretreated advanced/metastatic ROS1+ solid tumors. Key objectives were selection of a recommended ph 2 dose (RP2D) and evaluation of safety and efficacy (RECIST 1.1, investigator assessment). Data cut: 12 March 2024. Results 104 pts (99 NSCLC, 5 other) received zidesamtinib (25-150 mg orally once daily [QD]) in ph 1. Pts had a median of 3 (range: 1-11) prior anticancer therapies, including any ROS1 TKI (99%); lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); ≥2 ROS1 TKIs (69%); and chemo (66%). 53% had history of CNS metastases (mets). 100 mg QD was selected as the RP2D with no observed dose relationships for safety or efficacy. No dose-limiting toxicity or discontinuation due to treatment-related adverse event (TRAE) occurred. TRAE led to dose reduction in 5.8%. Most common TRAEs were peripheral edema (18%) and transaminase increase (12%); TRAEs were grade ≥3 in 7.7%. 73 pts with ROS1+ NSCLC were response-evaluable (Table). In pts with known ROS1 G2032R, ORR was 65% (11/17) with mDOR 15.8m (6, NE) among repo-naïve pts and ORR was 38% (3/8) among repo-pretreated pts. In pts with measurable intracranial (IC) mets and ≥2 prior ROS1 TKIs (all with prior lorlatinib and/or repo), IC ORR was 57% (4/7), and IC DOR range was 1.9+ - 17.3+m with no IC progression. Conclusions Zidesamtinib demonstrated encouraging efficacy and durability in pts with pretreated ROS1+ NSCLC, including those who had exhausted available therapies, with ROS1 resistance mutations including G2032R, and/or with CNS mets. Safety was favorable and consistent with the highly ROS1-selective and TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent in pts with TKI-naïve and pretreated ROS1+ NSCLC. Clinical trial identification NCT05118789.

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