Abstract Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 TKI approved by the US FDA for the treatment of patients (pts) with locally advanced/metastatic ROS1+ NSCLC. Taletrectinib has shown robust efficacy, including intracranial (IC) activity, and a tolerable safety profile in both TKI-naïve and TKI-pretreated pts with ROS1+ NSCLC in the Phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) studies (Pérol M, et al. J Clin Oncol 2025). Here we report updated data for taletrectinib in TKI-naïve pts with ∼3 years of follow-up. Methods: The TRUST-I and TRUST-II study designs have been previously reported (Pérol M, et al. J Clin Oncol 2025). The efficacy population included pts from TRUST-I and TRUST-II with ≥1 measurable baseline lesion per RECIST v1. 1 by independent review committee. Safety was evaluated in pts with ROS1+ NSCLC from Phase 1 and 2 trials who received ≥1 dose of taletrectinib 600 mg once daily. Results: As of Aug 31, 2025, the pooled efficacy analysis included 157 TKI-naïve pts (103 from TRUST-I; 54 from TRUST-II). With a median (m) follow-up of 35. 5 months (mo), confirmed ORR was 89. 8% (95% CI 84. 0-94. 1), mDOR was 49. 7 mo (95% CI 38. 6-NR), mPFS was 46. 1 mo (95% CI 31. 8-NR), and IC-ORR was 76. 5% (95% CI 50. 1-93. 2). Data by trial are shown in the Table. Overall, there were no new safety signals, and safety was consistent between TKI-naïve pts and the safety population (n=363). Conclusions: With ∼3 years of follow-up in the pooled analysis and 4 years of follow-up in TRUST-I, taletrectinib demonstrated high and durable response rates in TKI-naïve pts with ROS1+ NSCLC, with a mDOR of 4 years. To the best of our knowledge, these results represent the highest ORR and longest DOR and PFS reported to date for an FDA-approved ROS1 TKI in this patient population. These data support taletrectinib as an effective and tolerable treatment option particularly in pts with advanced ROS1+ NSCLC who have not received a prior ROS1 TKI. Citation Format: Lyudmila Bazhenova, Jorge Nieva, Misako Nagasaka, Hidetoshi Hayashi, Qitao Yu, Scott Owen, Maurice Pérol, Feiwu Ran, Wei Wang, Xianyu Zhang, Michael Chen, Wei Li, Geoffrey Liu, Caicun Zhou. Taletrectinib in tyrosine kinase inhibitor (TKI) -naïve patients with ROS1+ non-small cell lung cancer (NSCLC): Updated data from TRUST-I and TRUST-II 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 CT300.
Bazhenova et al. (Fri,) studied this question.