Taletrectinib, a next generation selective ROS1 inhibitor, demonstrates a differentiated profile in ROS1 fusion models

ROS1 fusions, present in approximately 2% of non-small cell lung cancer (NSCLC) patients, drive cancer cell growth and survival. FDA-approved tyrosine kinase inhibitors (TKI) for ROS1 fusion positive NSCLC include crizotinib, entrectinib, repotrectinib, and more recently, taletrectinib. However, resistance mechanisms such as secondary kinase-domain mutations (e.g., ROS1-G2032R) limit the efficacy of crizotinib and entrectinib, while repotrectinib can cause central nervous system (CNS) adverse reactions including dizziness, ataxia and cognitive impairment, attributed to the inhibition of tropomyosin receptor kinase B, TRKB. Taletrectinib is a potent, CNS-active, selective, next-generation ROS1 inhibitor for the treatment of patients with locally advanced or metastatic ROS1-positive NSCLC. Taletrectinib is currently approved by the US FDA and is also approved in China and Japan. As of Jun 7, 2024, pooled results from the TRUST-I and TRUST-II studies of taletrectinib demonstrated a confirmed objective response rate (cORR) of 88.8%, an intracranial cORR of 76.5%, a median duration of response (mDOR) of 44.2 months and a median progression free survival (mPFS) of 45.6 months in patients with advanced ROS1-positive NSCLC that have not previously received a ROS1 TKI. Durable responses were also reported in patients who had previously been treated with a TKI (Pérol M, et al. J Clin Oncol . 2025). Herein, we describe taletrectinib and its differentiated profile in comparison to other approved ROS1 inhibitors. At clinically relevant concentrations, taletrectinib demonstrated complete inhibition of ROS1 wild type and ROS1 G2032R in vitro and inhibited the growth of cell lines harboring single and double mutations in ROS1. Mechanistic studies revealed that taletrectinib inhibited the expression of key markers associated with the epithelial to mesenchymal transition (EMT) pathway and inhibited the migration of lung cancer cells indicating that taletrectinib could potentially inhibit the invasive capacity of lung cancer cells. Taletrectinib treatment also induced tumor regressions in several in vivo ROS1 fusion models, regardless of the fusion partner. In summary, our nonclinical data demonstrate that, at clinically relevant concentrations, taletrectinib exhibits activity in ROS1 wild-type and mutant-driven cancers and has a distinct profile that addresses the unmet needs of ROS1-positive NSCLC patients.