FDA Approves Taletrectinib for ROS1+ Advanced NSCLC

FDA

The FDA has approved taletrectinib (Ibtrozi) for the treatment of patients with locally advanced or metastatic, ROS1-positive non–small cell lung cancer.1,2

The regulatory decision was supported by data from the phase 2 TRUST-1 (NCT04395677) and TRUST-II (NCT04919811) trials.1 Treatment-naive patients experienced an overall response rate (ORR) of 90% (95% CI, 83%-95%) in TRUST-I and 85% (95% CI, 73%-93%) in TRUST-II. In patients previously treated with a TKI, the ORR was 52% (95% CI, 39%-64%) in TRUST-I and 62% (95% CI, 46%-75%) in TRUST-II.

“Patients living with advanced ROS1-positive NSCLC and their health care providers are in need of new treatment options,” Nathan Pennell, MD, PhD, a professor of medicine at Cleveland Clinic in Ohio, stated in a news release.2 “[Taletrectinib's] durability of response and ability to effectively penetrate the brain, coupled with a well-characterized and manageable safety profile, further addresses these critical needs for patients. I believe this now-approved therapy offers providers and patients a promising new option for the treatment of advanced ROS1-positive NSCLC.”

Talking About TRUST-I and TRUST-II: Design, Treatment, and Objectives

TRUST-I was an open-label, single-arm, nonrandomized study done in China; it comprised two cohorts of patients with locally advanced or metastatic ROS1-positive NSCLC.3 Cohort 1 included TKI-naive patients, and cohort 2 included those who had progressed on crizotinib (Xalkori), which was the only ROS1 TKI that had been approved in China during the trial. TRUST-II was a global, multicenter, open-label, single-arm, nonrandomized study which also had two cohorts; cohort 1 included those with TKI-naive ROS1-positive NSCLC and cohort 2 included pretreated patients who had previously received 1 approved ROS1 TKI in the form of crizotinib or entrectinib (Rozlytrek).

Key eligibility criteria across cohorts included having advanced NSCLC, at least 1 measurable lesion by RECIST 1.1 criteria at baseline, locally documented evidence of a ROS1 gene fusion, an ECOG performance status no higher than 1, and acceptable hepatic, renal, and bone marrow function. Brain metastases were permitted if patients were asymptomatic or if prior treatment led to clinical stability.

All patients received taletrectinib at a once-daily dose of 600 mg as part of a 21-day treatment cycle. Treatment continued until progressive disease, intolerable toxicity, withdrawn consent, or death.

The primary end point in both trials was confirmed ORR per RECIST 1.1 criteria and independent review committee (IRC) assessment. Secondary end points included disease control rate (DCR), duration of response (DOR), time to response (TTR), and progression-free survival (PFS). In those with measurable baseline brain metastases, confirmed intracranial ORR (IC-ORR) and DCR were evaluated by IRC and per modified RECIST 1.1 criteria. Safety was also assessed.

Additional Efficacy Findings

In response-evaluable patients who were TKI naive, the DCR was 95.0% (95% CI, 90.4%-97.8%). At a median follow-up of 21.2 months, the median DOR in those with confirmed responses was 44.2 months (95% CI, 30.4-not reached [NR]); the estimated DOR rate at 36 months was 57.7% (95% CI, 45.0%-68.5%). Moreover, the median TTR was 1.4 months (95% CI, 1.4-1.4). The median PFS was 45.6 months (95% CI, 29.0-NR) and the median OS was NR; the estimated 36-month PFS and OS rates were 52.6% (95% CI, 41.0%-62.9%) and 66.3% (95% CI, 55.3%-75.2%), respectively.

In response-evaluable patients who were TKI pretreated, the DCR was 87.6% (95% CI, 80.1%-93.1%). At a median follow-up of 21.0 months, the median DOR in those who had confirmed responses to the agent was 16.6 months (95% CI, 10.6-27.3); the estimated DOR rate at 12 months was 61.1% (95% CI, 46.3%-73.1%). Additionally, the median TTR in this group was 1.4 months (95% CI, 1.4-1.4). The median PFS was 9.7 months (95% CI, 7.4-12.0) and the median OS was NR; the respective 12-month PFS and OS rates were 39.7% (95% CI, 29.6%-49.6%) and 77.5% (95% CI, 68.1%-84.5%).

In those with measurable brain metastases, the IC-ORR with taletrectinib was 76.5% (95% CI, 50.1%-93.2%) and the IC-DCR was 88.2% (95% CI, 63.6%-98.5%). At a median follow-up of 22.6 months, the IC-DOR was 14.7 months (95% CI, 4.2-30.2). In TKI-pretreated patients who had measurable baseline brain metastases, the IC-ORR was 65.6% (95% CI, 46.8%-81.4%); in this group, the IC-DCR was 93.8% (95% CI, 79.2%-99.2%). The IC-DOR was 11.9 months (95% CI, 6.9-23.5) at a median follow-up of 19.6 months.

Safety Spotlight

Safety was examined in a total of 352 patients who received the agent at a once-daily dose of 600 mg. The most common treatment-emergent adverse effects (TEAEs) were increased aspartate aminotransferase (AST) levels (72%), increased alanine aminotransferase (ALT) levels (68%), diarrhea (64%), nausea (46%), and vomiting (44%). Neurologic effects that were reported in at least 10% of patients included dizziness (21%), dysgeusia (15%), and headache (11%). TEAEs led to treatment discontinuation for 7% of patients, and 3% of them were determined to be related to treatment.

The most common treatment-related AEs included increased AST levels (70%), increased ALT levels (67%), diarrhea (61%), nausea (44%), and vomiting (41%).

References

1. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. FDA. June 11, 2025. Accessed June 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-taletrectinib-ros1-positive-non-small-cell-lung-cancer
2. U.S. Food and Drug Administration approves Nuvation Bio’s Ibtrozi (taletrectinib), a next-generation oral treatment for advanced ROS1-positive non-small cell lung cancer. News release. Nuvation Bio. June 11, 2025. Accessed June 11, 2025. https://investors.nuvationbio.com/news/news-details/2025/U-S--Food-and-Drug-Administration-Approves-Nuvation-Bios-IBTROZI-taletrectinib-a-Next-Generation-Oral-Treatment-for-Advanced-ROS1-Positive-Non-Small-Cell-Lung-Cancer/default.aspx
3. Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1+ non–small cell lung cancer: TRUST. J Clin Oncol. 2025;43(16):1920-1929. doi:10.1200/JCO-25-00275