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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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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
ROS1 fusion lung non-small cell carcinoma predicted - sensitive NUV-520 Phase I Actionable In a Phase I trial (ARROS-1), NUV-520 treatment demonstrated safety and activity in patients with non-small cell lung cancer harboring a ROS1 fusion, resulting in a response rate of 38% (28/73), including a complete response in 2 patients with a duration of response of at least 16.6 mo and 23.5 mo, and median DOR was not reached (Ann Oncol (2024) 35 (Suppl_2): S804-S805; NCT05118789). detail...