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FDA approves taletrectinib for ROS1-positive advanced non-small cell lung cancer

On June 11, 2025, the U.S. Food and Drug Administration (FDA) has approved taletrectinib, an oral next-generation ROS1-selective tyrosine kinase inhibitor (TKI), for adults with ROS1-positive advanced non-small cell lung cancer (NSCLC), regardless of prior TKI exposure.1

While ROS1 rearrangements occur in only 1–2% of NSCLC cases, they represent a molecular subtype with distinct therapeutic targets. First-generation TKIs like crizotinib have improved outcomes but are limited by CNS progression, off-target resistance, and on-target mutations such as G2032R.2 Newer agents like entrectinib and repotrectinib address some of these issues but either show marginal efficacy or are associated with frequent neurologic adverse events.3, 4 These limitations underscore the need for a treatment that combines potent systemic and intracranial efficacy with a favorable safety profile,an unmet need taletrectinib appears to address.

The FDA approval was based on pooled results from the Phase II TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials. Patients received taletrectinib 600 mg daily. In TKI-naïve patients (n=160), the overall response rate (ORR) was 88.8% (95% CI, 82.8–93.2), with a median duration of response (DOR) of 44.2 months (95% CI, 30.4–NR) and progression-free survival (PFS) of 45.6 months (95% CI, 29.0–NR). In TKI-pretreated patients (n=113), ORR was 55.8% (95% CI, 46.1–65.1), with a median DOR of 16.6 months (95% CI, 10.6–27.3) and PFS of 9.7 months (95% CI, 7.4–12.0). Notably, among patients with the G2032R mutation (n=13), ORR was 61.5% (95% CI, 31.6–86.1). Intracranial efficacy was also encouraging, with IC-ORRs of 76.5% (95% CI, 50.1–93.2; n=17) in TKI-naïve and 65.6% (95% CI, 46.8–81.4; n=32) in pretreated patients.5

Treatment-emergent adverse events (TEAEs) were manageable. Grade ≥3 TEASs occurred in 51.6%, with low rates of neurologic AEs (mild dizziness [21%]) and treatment discontinuation (6.5%).5

In our conversation with Misako Nagasaka, MD, UCI Health Chao Family Comprehensive Cancer Center, Orange, CA, she emphasized that taletrectinib showed superior efficacy over crizotinib in a matching-adjusted indirect comparison (MAIC) analysis, with ORR of 90.1% vs. 71.7% and significantly lower risks of progression and death.6 Taletrectinib’s approval marks a major advance for ROS1-positive NSCLC, offering a well-tolerated, CNS-active option with durable responses across treatment lines.

References:

  1. Center for Drug Evaluation and Research. FDA approves taletrectinib for ROS1+ NSCLC [Internet]. FDA; [cited ]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-taletrectinib-ros1-positive-non-small-cell-lung-cancer
  2. Gendarme S, Bylicki O, Chouaid C, Guisier F., ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date. 2022 Jan; 29(2). DOI: 10.3390/curroncol29020057.
  3. Drilon A, Chiu CH, Fan Y, Cho BC, Lu S, Ahn MJ, et al., Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC. 2022 Apr;3(6). DOI: 10.1016/j.jtocrr.2022.100332.
  4. Drilon A, Camidge DR, Lin JJ, Kim SW, Solomon BJ, et al., Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. 2024 Jan;390(2). DOI: 10.1056/NEJMoa2302299.
  5. Maurice Pérol, Wei Li, Nathan A. Pennell, Geoffrey Liu, et al., Taletrectinib in ROS1+ Non–Small Cell Lung Cancer: TRUST. 2025 Apr; 0. DOI:10.1200/JCO-25-00275
  6. Misako Nagasaka, Geoffrey Liu, Nathan A. Pennell, Maurice Perolm et al., LBA2: Taletrectinib vs crizotinib in ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC): A mathicng-adjusted indirect comparison (MAIC). 2025 Mar; 20(3). DOI: 10.1016/S1556-0864(25)00195-9