Taletrectinib Data Published as FDA Weighs Approval for ROS1+ NSCLC

Holographic concept of lung cancer: © catalin - stock.adobe.com

Pivotal data showing strong clinical activity for taletrectinib in patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC) were published in the Journal of Clinical Oncology, with the FDA currently reviewing a new drug application (NDA) for use of the ROS1 tyrosine kinase inhibitor (TKI) in this setting.^1,2

The data are from a pooled analysis of the single-arm, open-label, multicenter phase 2 TRUST-I and TRUST-II trials. Overall, there were 273 patients with ROS1 fusion–positive NSCLC in the efficacy evaluable population. The confirmed objective response rate (cORR) was 88.8% among patients with no prior TKI treatment (n = 160) and 55.8% among patients previously treated with ROS1 TKI (n = 113). The intracranial (IC)-ORR was 76.5% and 65.6%, respectively, and the median duration of response was 44.2 months and 16.6 months, respectively.

The median progression-free survival (PFS) in TKI-naïve patients was 45.6 months compared with 9.7 months in patients who had received ROS1 TKI. Also of note, among patients with a G2032R mutation—the most common acquired resistance mutation to ROS1-targeted therapy—the cORR was 61.5% (8 of 13).

The safety of taletrectinib for the pooled analysis was assessed in 352 patients treated with the TKI at 600 mg once daily. Common treatment-emergent adverse events (TEAEs)—which were grade 1 for the most part—were GI events (88%) and elevated aspartate aminotransferase (72%) and alanine aminotransferase (68%). Neurologic TEAEs were also mostly grade 1 and included dizziness (21%) and dysgeusia (15%). TEAE-related discontinuations occurred in 6.5% of patients.

Data from the study were previously shared at the 2024 European Society for Medical Oncology Congress.³ Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision regarding the NDA for use of taletrectinib in ROS1-positive NSCLC on or before June 23, 2025.

“This integrated analysis further validated the efficacy and safety profile of taletrectinib from the TRUST-I trial and confirmed that the results were generalizable to the global population of patients with ROS1+ NSCLC. Additional follow-up on long-term survival is ongoing,” the study authors wrote.

TRUST-I/TRUST-II Pooled Analysis Details

The median age of the efficacy analysis population of 273 patients with ROS1-positive NSCLC was 56.0 years (range, 26-82). Overall, 57.1% of patients were female, 66.7% had never smoked, and 93.8% had stage IV adenocarcinoma. Patients had an ECOG performance status of 0 (29.7%) or 1 (70.3%).

About one-fourth (23.1%) of the pooled TKI-naïve group had brain metastasis at baseline and 20% had received prior chemotherapy. In this pooled prior-TKI treated group, these rates were 48.7% and 37.2%, respectively. Most (91.2%) of the TKI-pretreated population had prior crizotinib (Xalkori) and 8.8% had prior entrectinib (Rozlytrek).

The primary end point for the pooled analysis was cORR per the assessment of an independent review committee. Among secondary end points were IC-ORR, PFS, duration of response, and safety.

Looking ahead, an actively recruiting phase 3 trial (NCT06564324) will be comparing taletrectinib head-to-head with crizotinib in TKI-naïve patients with locally advanced or metastatic ROS1-positive NSCLC.

References

1. Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1+ Non-Small Cell Lung Cancer: TRUST [published online ahead of print April 3, 2025]. J Clin Oncol. doi: 10.1200/JCO-25-00275.

2. U.S. Food and Drug Administration accepts for priority review Nuvation Bio’s new drug application for taletrectinib for the treatment of advanced ROS1-positive non-small cell lung cancer. News release. Nuvation Bio. December 23, 2024. Accessed April 8, 2025. https://tinyurl.com/2wn48da4

3. Pérol M, Li W, Pennell NA, et al. Pooled efficacy and safety from 2 pivotal phase II trials of taletrectinib in patients (pts) with advanced or metastatic ROS1+ non-small cell lung cancer (NSCLC). Ann Oncol. 2024;35(suppl 2):S821. doi:10.1016/j.annonc.2024.08.1346