Taletrectinib Demonstrates Durable Responses in TKI-Naive and -Pretreated ROS1+ NSCLC

Taletrectinib (Ibtrozi) demonstrated clinically meaningful efficacy in patients with ROS1-positive non–small cell lung cancer (NSCLC), according to updated findings from the phase 2 TRUST-II trial (NCT04919811) presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.

At a median follow-up of 20.5 months (range, 8.3-34.5), treatment with taletrectinib in the TKI-naive cohort (n = 54) led to a confirmed overall response rate (cORR) of 85.2% (95% CI, 72.9%-93.4%). The cORR in those who previously received chemotherapy (n = 9/10) experienced was 90.0% vs 84.1% for those who had not (n = 37/44). The median time to response (TTR) was 1.4 months (95% CI, 1.3-3.4) and the median duration of response (DOR) was not reached (NR; 95% CI, 20.6-NR). The 12- and 18-month DOR rates were 74% and 68%, respectively. Moreover, the median progression-free survival (PFS) was also not reached (95% CI, 15.9-NR); 12- and 18-month PFS rates were 73% and 61%, respectively. Intracranial efficacy was examined in 9 patients, and the intracranial cORR (IC-ORR) was 66.7% (95% CI, 29.9%-92.5%).

In the TKI-pretreated cohort (n = 47), at a median follow-up of 20.4 months (range, 8.6-34.5), taletrectinib elicited a cORR of 61.7% (95% CI, 46.4%-75.5%), with a median TTR of 1.4 months (95% CI, 1.4-1.6). By prior chemotherapy exposure, the cORR was 78.9% in patients who had received prior chemotherapy (n = 15/19) and 50.0% in those without prior chemotherapy (n = 14/28). The median DOR was 19.4 months (95% CI, 10.7 months-not evaluable); the 12- and 18-month DOR rates were 68% and 56%, respectively. The median PFS was 11.8 months (95% CI, 7.7-20.6), with 12- and 18-month PFS rates of 42% and 35%, respectively. Intracranial activity was examined in 16 patients, and the IC-ORR was 56.3% (95% CI, 29.9%-80.3%).

“Responses to taletrectinib remain durable and encouraging. PFS [and] overall survival [OS; data] remain immature. Taletrectinib demonstrated a favorable safety profile [with] low rates of neurologic [adverse effects (AEs)] and treatment discontinuation,” Geoffrey Liu, MD, MSc, lead study author and senior scientist at Princess Margaret Cancer Centre, shared in a presentation of the data. “Post FDA approval, these results further support [taletrectinib] as an effective treatment option [for] patients with advanced ROS1-positive NSCLC, regardless of prior TKI experience.”

What Is the Design of the TRUST-II Study Examining Taletrectinib?

TRUST-II is a global, phase 2, multicenter, single-arm, open-label study that enrolled patients with locally advanced or metastatic disease harboring a ROS1 fusion who were at least 18 years of age and an ECOG performance status of 0 or 1.^1,2

Patients were stratified into two main cohorts: cohort 1 included TKI-naive patients and cohort 2 included those previously treated with a ROS1 TKI. Taletrectinib was administered orally at 600 mg once daily.

The primary end point was independent review committee–assessed ORR per RECIST v1.1 criteria. Secondary end points included DOR, IC-ORR, PFS, OS, TTR, and safety outcomes.

In June 2025, the FDA approved taletrectinib for use in patients with locally advanced or metastatic ROS1-positive NSCLC based on findings from the phase 2 TRUST-I (NCT04395677) and TRUST-II studies.^3,4 The agent induced an ORR of 90% (95% CI, 83%-95%) in treatment-naive patients enrolled to TRUST-I; this rate was 85% (95% CI, 73%-93%) in those enrolled to TRUST-II. In patients with prior exposure to a TKI in the respective studies, the ORRs were 52% (95% CI, 39%-64%) and 62% (95% CI, 46%-75%).

The median patient age was 57.0 years (range, 27-83) in the TKI-naive cohort and 55.5 years (range, 27-79) in the TKI-pretreated cohort.¹ Females comprised 56.4% and 54.0% of patients in these respective groups. With respect to smoking history, 50.9% of patients in the TKI-naive cohort and 60% in the TKI-pretreated cohort had never smoked. The majority of patients in the TKI-naive group were enrolled from Asia (61.8% vs 38.2% non-Asia), whereas the TKI-pretreated group had a higher proportion of patients from non-Asia regions (56.0% vs 44.0% Asia). In the TKI-naive group, a higher proportion of patients had an ECOG performance status of 1 vs 0 (60.0% vs 40.0%); this was also the case for the TKI-pretreated group (52.0% vs 48.0%).

Most patients presented with stage IV disease, including 89.1% in the TKI-naive cohort and 98.0% in the TKI-pretreated cohort. Prior chemotherapy was more common in the pretreated group (38.0%) compared with the naive group (20.0%). Baseline brain metastases were observed in 34.5% of patients in the TKI-naive cohort and 56.0% of those in the pretreated cohort. Among patients in the TKI-pretreated group, 80.0% had previously received crizotinib (Xalkori) and 20.0% had received entrectinib (Rozlytrek).

What Was the Toxicity Profile of Taletrectinib?

Of the 171 patients evaluable for safety, 98.8% experienced treatment-emergent AEs (TEAEs), with 52.6% experiencing grade 3 or higher AEs. The most common any-grade TEAEs reported in at least 15% of patients included elevated alanine aminotransferase (ALT) levels (67.3%), elevated aspartate aminotransferase (AST) levels (65.5%), diarrhea (57.9%), nausea (52.0%), vomiting (34.5%), constipation (24.0%), anemia (19.9%), increased creatine phosphokinase (19.9%), dysgeusia (19.3%), dizziness (17.5%), QT prolongation (16.4%), and decreased appetite (15.2%).

Grade 3 or higher AEs that were most frequently observed included increased ALT levels (15.2%), increased AST levels (7.0%), anemia (4.1%), and QT prolongation (3.5%). Other grade 3 or higher effects included diarrhea, nausea, vomiting, and decreased appetite (all <2%).

Neurologic TEAEs were uncommon and primarily low grade, with grade 1 and 2 dysgeusia occurring in 15.2% and 4.1% of patients, respectively, and grade 1 and 2 dizziness reported in 15.2% and 2.3% of patients. Overall, 2.3% of patients discontinued treatment due to treatment-related AEs. Notably, no discontinuations were attributed to increased ALT or AST levels.

Disclosures: No disclosures were listed for Liu.

References

1. Liu G, Choi C, Sugawara S, et al. Updated efficacy and safety of taletrectinib in patients with ROS1+ non–small cell lung cancer: the global TRUST-II study. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA14.05.
2. Taletrectinib phase 2 global study in ROS1 positive NSCLC (TRUST-II). Clinicaltrials.gov. Updated November 11, 2024. Accessed September 8, 2025. https://www.clinicaltrials.gov/study/NCT04919811
3. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. FDA. June 11, 2025. Accessed September 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-taletrectinib-ros1-positive-non-small-cell-lung-cancer
4. 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 September 8, 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