Abstract Introduction: Preclinical data indicates that the investigational ROS1 TKI zidesamtinib offers improved potency against ROS1, including ROS1 G2032R resistance mutation, brain penetrance and TRK selectivity over FDA-approved dual TRK/ROS1 TKIs repotrectinib and taletrectinib. Maximizing ROS1 activity in the clinical setting, including activity in the CNS, is essential to drive clinically meaningful responses to treatment. ARROS-1 is evaluating zidesamtinib in patients (pts) with advanced/metastatic ROS1+ NSCLC and other solid tumors. Here we report data in pts with NSCLC previously treated with repotrectinib or taletrectinib. Methods: Key study endpoints in the global, single arm, phase 1/2 ARROS-1 trial (NCT05118789) include objective response rate (ORR, RECIST v1. 1 by BICR), duration of response (DOR), intracranial ORR (IC-ORR), and safety. This efficacy analysis included repotrectinib or taletrectinib previously-treated pts with ROS1+ NSCLC and measurable disease by BICR, treated with zidesamtinib 100 mg QD. Data cut-off: 22 Sep 2025. Results: At baseline, efficacy evaluable pts (results in Table) with prior repotrectinib (n=46) or taletrectinib (n=19) received a median of 2 prior ROS1 TKIs (range 1-4 for either) and 3 prior anticancer therapies (range 1-7 and 1-6, respectively) ; 63% and 53% received prior chemo. ROS1 resistance mutations by local or central testing were reported in 35% and 42%; active CNS disease in 46% and 53%. The safety profiles in these pt groups were consistent with what was previously reported in the overall pivotal TKI pretreated study population, including the avoidance of TRK or neurological adverse events (Drilon AE, et al. J Thorac Oncol. 2025;20 (10) (Suppl 3): S3). Conclusions: The meaningful clinical activity presented here for zidesamtinib, including in pts with CNS disease and ROS1 G2032R resistance mutation, indicates that many ROS1+ NSCLCs remain ROS1-dependent beyond repotrectinib and taletrectinib. Citation Format: Geoffrey Liu, Alexander E. Drilon, Benjamin Besse, Gianluca Spitaleri, Jessica J. Lin, Byoung Chul Cho, Tatsuya Yoshida, Daniel Haggstrom, Steven Kao, Aurelie Swalduz, Misako Nagasaka, Benjamin J. Solomon, Lorenza Landi, Chiara Bennati, Elvire Pons-Tostivint, Christophe Dooms, A. J. van der Wekken, Saiama Waqar, Shirish Gadgeel, Chia-Chi Lin, Tetsuro Kondo, Hidetoshi Hayashi, Daniel Tan, Giulia Pasello, Matteo Duca, Luis G. Paz-Ares, Antonio Calles, Enriqueta Felip, Julien Mazieres, Adrianus Johannes de Langen, Alice T. Shaw, Jonathan W. Riess, Marina Garassino, Elaine Shum, Christina S. Baik, Jessica R. Bauman, D. Ross Camidge, Chien-Chung Lin, Gee-Chen Chang, Dong-Wan Kim, Myung-Ju Ahn, Ji-Youn Han, Kiichiro Ninomiya, Ryo Ariyasu, Ross Andrew Soo, Sanjay Popat, Jürgen Wolf, Maria Rosario García Campelo, Vivek A. Upadhyay, Stephen V. Liu. Zidesamtinib in patients with ROS1+ NSCLC previously treated with repotrectinib or taletrectinib abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT248.
Liu et al. (Fri,) studied this question.