China's National Medical Products Administration (NMPA) has approved taletrectinib adipate (Dovbleron), a next-generation ROS1 tyrosine kinase inhibitor (TKI), for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who have been previously treated with ROS1 TKIs. This approval marks a significant advancement in the treatment landscape for this patient population, addressing the challenges of resistance and disease progression.
The regulatory decision was based on the multicenter, open-label, single-arm, phase 2 TRUST-I trial (NCT04395677), which investigated taletrectinib in Chinese patients with advanced ROS1-positive NSCLC. The results, presented at the 2024 ASCO Annual Meeting, demonstrated a confirmed overall response rate (ORR) of 51.5% (95% CI, 38.88%-64.01%) in patients pretreated with crizotinib (Xalkori; n = 66). The disease control rate (DCR) was 83.3% (95% CI, 72.13%-91.38%). The median time to response (TTR) was 1.4 months (95% CI, 1.38-1.41), and at a median follow-up of 9.7 months, the median duration of response (DOR) was 10.6 months (95% CI, 6.3-not reached). The median progression-free survival (PFS) was 7.6 months (95% CI, 5.5-12.0), with a 9-month PFS rate of 47.4%.
Clinical Efficacy and Safety Profile
Caicun Zhou, MD, PhD, director of the Department of Oncology at Shanghai East Hospital, Tongji University, noted that taletrectinib demonstrated significant therapeutic effects on brain lesions and efficacy in crizotinib-resistant disease. The favorable safety profile and tolerability, with low rates of dose reduction and treatment discontinuation due to adverse effects (AEs), further support its potential as a valuable treatment option.
First-Line Treatment Potential
In addition to the approval for previously treated patients, a second NDA for taletrectinib was accepted and granted priority review designation by China’s NMPA for patients with locally advanced or metastatic ROS1-positive NSCLC who have not previously been treated with ROS1 TKIs. This NDA was supported by data from another cohort of patients treated in the TRUST-I trial. Among 106 patients with ROS1 TKI–naive NSCLC, the confirmed ORR per IRC was 90.6% (95% CI, 83.33%-95.38%). The DCR was 95.3% (95% CI, 89.33%-98.45%), and the median TTR was 1.4 months (95% CI, 1.38-1.41). At a median follow-up of 23.5 months, the median DOR and PFS per IRC assessment were both not yet reached, and the respective 24-month DOR and PFS rates were 78.6% and 70.5%.
TRUST-I Trial Design
The TRUST-1 trial enrolled patients at least 18 years of age with locally advanced or metastatic NSCLC harboring a ROS1 fusion and an ECOG performance status of 0 or 1. Patients were divided into two cohorts: Cohort A included patients naive to a ROS1 TKI, and Cohort B featured patients who were previously treated with crizotinib. Patients in both cohorts received taletrectinib at 600 mg once per day. The primary endpoint was confirmed ORR per RECIST 1.1 criteria as assessed by an independent review committee. Secondary endpoints included DOR, intracranial ORR, best overall response, DCR, TTR, PFS, and safety.
FDA and NMPA Designations
Taletrectinib has received orphan drug designation from the FDA for the treatment of patients with ROS1-positive NSCLC and breakthrough therapy designation from both the United States FDA and China’s NMPA for patients with locally advanced or metastatic ROS1-positive NSCLC. The FDA also granted priority review to an NDA for taletrectinib for the line-agnostic treatment of patients with advanced ROS1-positive NSCLC, based on pooled findings from the TRUST-I and phase 2 TRUST-II (NCT04919811) trials.
Global TRUST-II Trial
Data from the global, single-arm, open-label TRUST-II trial, presented at the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC), demonstrated that at a median follow-up of 15.8 months, patients in the TKI-naive cohort (n = 54) achieved a confirmed ORR of 85.2% (95% CI, 72.88%-93.38%). In the TKI-pretreated cohort (n = 47), the confirmed ORR was 61.7% (95% CI, 46.38%-75.49%).
Safety and Tolerability
Across the TRUST-I and TRUST-II trials, taletrectinib demonstrated a manageable safety profile. Common treatment-emergent adverse events (TEAEs) included increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and diarrhea. Neurologic TEAEs were low, with dizziness and dysgeusia reported at low rates.
Expert Commentary
Stephen Liu, MD, director of Thoracic Oncology and Developmental Therapeutics at Georgetown Lombardi Comprehensive Cancer Center, noted the potential for taletrectinib to be a best-in-class drug, citing its high response rates and favorable safety profile. Tony S. K. Mok, MD, FASCO, chairman of the Department of Clinical Oncology, Chinese University of Hong Kong, suggested that taletrectinib could be considered as an option for first-line treatment of patients with ROS1-positive lung cancer.
The approval of taletrectinib in China represents a significant step forward in the treatment of ROS1-positive NSCLC, offering a new option for patients who have progressed on prior TKIs and demonstrating promising efficacy as a first-line therapy.
