In an integrated analysis from TRUST-I and TRUST-II trials, taletrectinib demonstrated high and durable overall and intracranial response rates and prolonged progression-free survival (PFS) in both tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients, with activity against G2032R acquired resistance mutations, establishing taletrectinib as a potential best-in-class ROS1 TKI for patients with advanced ROS1 fusion-positive non-small cell lung cancer (NSCLC).
This integrated analysis further validated the efficacy and safety profile of taletrectinib from the TRUST-I and confirmed that the results were generalisable to the global population of patients with ROS1 fusion-positive NSCLC. Additional follow-up on long-term survival is ongoing. The findings were published by Prof. Caicun Zhou of the Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine and Department of Medical Oncology, East Hospital, Tongji University School of Medicine in Shanghai, China and colleagues on 3 April 2025 in the JCO.
ROS1 fusions are rare genetic events reported in multiple solid tumours, including NSCLC, where the prevalence is 0.9% to 2.6%. Patients with ROS1 fusion-positive NSCLC tend to be female, are younger than patients without driver alterations, are diagnosed at an advanced stage (III-IV), have adenocarcinoma, and most are never smokers. Approximately one third of patients with ROS1 fusion-positive NSCLC have a brain metastasis at diagnosis, which can be as high as 50% in previously treated patients.
The authors wrote in the background that patients treated with first-generation TKIs progress because of off-target bypass pathway activation, leading to refractory disease, development of on-target acquired resistance mutations such as G2032R, or brain metastases. Currently, three TKIs are approved by the US Food and Drug Administration for ROS1 fusion-positive NSCLC: crizotinib, entrectinib, and repotrectinib.
Taletrectinib is an oral, central nervous system-active, next-generation ROS1 TKI with 11-20 fold selectivity over TrKB, which may translate into lower rates of, less severe, or limited spectrum of neurologic adverse events (AEs). The recommended phase II dose of 600 mg once daily was established in two phase I trials conducted in the US and Japan and confirmed during the safety lead-in of TRUST-I. A pooled population pharmacokinetics (PK) analysis indicated that population PK of taletrectinib is similar in US and Japanese phase I studies.
An integrated analysis using registrational cohorts from the pivotal phase II regional TRUST-I and global TRUST-II trials was performed to increase the number of patients and provide a more reliable estimation of treatment effects, as well as examine if the efficacy and safety results observed in TRUST-I were generalisable to a global population of patients with ROS1 fusion-positive NSCLC.
This integrated analysis is feasible because both studies had similar pivotal study designs, inclusion and exclusion criteria, and primary and secondary endpoints. In addition, the efficacy and safety assessment methods and their schedules were identical, and statistical approaches were consistent between these studies.
TRUST-I and TRUST-II were phase II, single-arm, open-label, non-randomised, multicentre trials. Efficacy outcomes were pooled from TRUST-I and TRUST-II pivotal cohorts. The safety population comprised all patients treated with once-daily oral taletrectinib 600 mg pooled across the taletrectinib clinical programme. The primary endpoint was independent review committee assessed confirmed objective response rate (ORR). Secondary outcomes included intracranial ORR, PFS, duration of response (DoR), and safety.
As of 7 June 2024, the efficacy-evaluable population included 273 patients in TRUST-I and TRUST-II. Among 160 TKI-naïve patients, confirmed ORR was 88.8% and intracranial confirmed ORR was 76.5%; in 113 TKI-pretreated patients, confirmed ORR was 55.8% and intracranial confirmed ORR was 65.6%. In TKI-naïve patients, the median DoR and median PFS were 44.2 and 45.6 months, respectively. In TKI-pretreated patients, the median DoR and median PFS were 16.6 and 9.7 months. Confirmed ORR in patients with G2032R mutation was 61.5% (8 of 13).
Among 352 patients treated with taletrectinib 600 mg once daily, the most frequent treatment-emergent (TE) AEs were gastrointestinal events (88%) and elevated AST (72%) and ALT (68%); most were grade 1. Neurologic TEAEs were infrequent (dizziness 21%, dysgeusia 15%) and mostly grade 1. TEAEs leading to discontinuations (6.5%) were low.
The authors concluded that taletrectinib showed a high response rate with durable responses, robust intracranial activity, prolonged PFS, favourable safety, and low rates of neurologic adverse events in TKI-naïve and pretreated patients. The safety and efficacy of taletrectinib will be directly compared with those of crizotinib in an ongoing phase III randomised study conducted in TKI-naïve patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.
The study findings were previously presented at the ESMO 2024 Congress in Barcelona, Spain (13-17 September 2024).
The study was supported by Nuvation Bio Inc.
Reference
Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1+ Non–Small Cell Lung Cancer: TRUST. JCO; Published online 3 April 2025. DOI: https://doi.org/10.1200/JCO-25-00275