Breaking Down Taletrectinib’s FDA Approval: Jorge J. Nieva, MD

Taletrectinib (Ibtrozi; Nuvation Bio Inc) was approved by the FDA on June 11 to treat ROS1-positive locally advanced or metastatic non–small cell lung cancer (NSCLC), based on results from the TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials.¹ These single-arm, multinational studies evaluated taletrectinib in both tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients, assessing its efficacy in first-line and resistant settings.^2,3

Notably, taletrectinib demonstrated a 90% response rate in TKI-naïve patients in TRUST-I and 85% in TRUST-II, marking a significant improvement over existing therapies like crizotinib (Xalkori; Pfizer) and entrectinib (Rozlytrek; Genentech). The corresponding durations of response at 12 months or more were 72% and 63%.⁴

Although cross-trial comparisons require caution, these high response rates position taletrectinib as a potential first-line standard, marking a novel approach for this subtype of NSCLC and its rare ROS1 mutation. In particular, taletrectinib has a favorable toxicity profile, with lower risk of central nervous system (CNS) toxicity compared with other therapeutics, although with a slightly higher rate of gastrointestinal (GI) effects. For clinicians, this balance may make it a preferred choice, as managing GI toxicity can be easier than CNS adverse effects.

Despite its advantages, access may vary globally, with crizotinib remaining the only option in some regions. However, in the US, taletrectinib is expected to join entrectinib and repotrectinib as a leading TKI for ROS1-positive NSCLC, offering personalized treatment based on toxicity tolerance. Its approval marks progress in targeting ROS1 resistance and improving outcomes for this subset of patients living with lung cancer.

In this interview with TRUST-I and TRUST-II investigator, Jorge J. Nieva, MD, associate professor of clinical medicine, Keck School of Medicine, and section head of thoracic and head and neck tumors, University of Southern California, he walks us through the design of the trials, the results that supported the FDA approval, and taletrectinib’s potential to redefine first-line therapy.

References

1. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. June 11, 2025. Accessed June 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-taletrectinib-ros1-positive-non-small-cell-lung-cancer
2. A study of AB-106 in subjects with advanced NSCLC harboring ROS1 fusion gene. ClinicalTrials.gov. Updated October 30, 2023. Accessed June 20, 2025. https://clinicaltrials.gov/study/NCT04395677
3. Taletrectinib phase 2 global study in ROS1 positive NSCLC (TRUST-II). ClinicalTrials.gov. Updated November 21, 2024. Accessed June 20, 2025. https://clinicaltrials.gov/study/NCT04919811
4. Shaw M. Taletrectinib approved for ROS1-positive NSCLC. AJMC^®. June 11, 2025. Accessed June 20, 2025. https://www.ajmc.com/view/taletrectinib-approved-for-ros1-positive-nsclc