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. In two Phase 2 studies, TRUST-I (NCT04395677) and TRUST-II (NCT04919811), taletrectinib showed robust efficacy, including intracranial (IC) activity and efficacy against G2032R mutations, and a tolerable safety profile in TKI-naïve and TKI-pretreated pts with ROS1+ NSCLC (Pérol M, et al. J Clin Oncol 2025). Here we report updated data in TKI-pretreated pts with ∼3 years of follow-up. Methods: The study designs of TRUST-I and TRUST-II 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. The safety population included pts with ROS1+ NSCLC from Phase 1 and 2 studies who received ≥1 dose of taletrectinib 600 mg once daily. Results: As of Aug 31, 2025, the pooled efficacy analysis included 113 TKI-pretreated pts (66 from TRUST-I prior crizotinib; 47 from TRUST-II 37 prior crizotinib, 10 prior entrectinib). With a median (m) follow-up of 35. 8 months (mo), confirmed ORR was 55. 8% (95% CI 46. 1-65. 1), mDOR was 16. 6 mo (95% CI 10. 7-24. 9), mPFS was 9. 7 mo (95% CI 7. 6-12. 0), and mOS was 29. 8 mo (95% CI 23. 2-46. 0). Responses were observed in pts with G2032R mutations (8/13; ORR 61. 5% 95% CI 31. 6-86. 1) and with CNS metastases (IC-ORR 65. 6% 95% CI 46. 8-81. 4). Data by trial are shown in the Table. Safety was similar between TKI-pretreated pts and the safety population (n=363). Conclusion: With longer follow-up, taletrectinib maintained durable responses in TKI-pretreated pts, including activity against CNS metastases and G2032R mutations, with a tolerable safety profile. These data support taletrectinib as an effective and tolerable treatment option for pts with ROS1+ NSCLC after prior TKI therapy. Citation Format: Geoffrey Liu, Jorge Nieva, Lyudmila Bazhenova, Chang-Min Choi, Qitao Yu, Shunichi Sugawara, Noriko Yanagitani, Filippo de Braud, Huijie Fan, Enriqueta Felip, Emilio Bria, Maurice Pérol, Feiwu Ran, Wei Wang, Xianyu Zhang, Michael Chen, Caicun Zhou. Taletrectinib in tyrosine kinase inhibitor (TKI) -pretreated 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 CT244.
Liu et al. (Fri,) studied this question.