Abstract 5612: Taletrectinib, a next generation selective ROS1 inhibitor, inhibits growth of ROS1 wild-type and ROS1-G2032R xenografts

Abstract The ROS1 gene is altered in approximately 2% of non-small cell lung cancer (NSCLC) patients. ROS1 fusions demonstrate ligand independent activity driving cell growth and survival. While several inhibitors for ROS1 have been FDA approved, including crizotinib, entrectinib and, more recently, repotrectinib, each present unique challenges. Resistance mechanisms such as secondary kinase-domain mutations including ROS1-G2032R can limit the efficacy of crizotinib and entrectinib, while repotrectinib can cause central nervous system (CNS) adverse reactions including dizziness, ataxia and cognitive impairment that have been attributed to inhibition of the tropomyosin receptor kinase B, TRKB. Therefore, a need remains for more tolerable and effective treatment options for ROS1 positive cancers.Taletrectinib is an oral, potent, selective and CNS-active next-generation ROS1 inhibitor specifically designed for the treatment of patients with ROS1-positive NSCLC. Herein, we describe taletrectinib and its activity in multiple in vitro and in vivo ROS1 fusion tumor models. Additionally, the antitumor activity of taletrectinib in comparison to other ROS1 inhibitors is examined. Taletrectinib exhibits selectivity for ROS1 over other kinases, including TRKB. Taletrectinib exhibits in vivo activity in models harboring ROS1 wild-type (ROS1-CD74, ROS1-SLC34A2) and ROS1-G2032R resistance mutation fusions (ROS1 G2032R-CD74, ROS1 G2032R-SLC34A2). Moreover, taletrectinib prolonged survival (>70 days) of mice implanted intracranially with a ROS1 fusion xenograft model. Our nonclinical data illustrates that taletrectinib has a profile which exhibits efficacy in ROS1 wild-type-, and mutant-driven cancers while maintaining selectivity against TRKB, resulting in an overall favorable profile. Taletrectinib is being evaluated in patients with locally advanced or metastatic ROS1-positive NSCLC in two Phase 2 single-arm pivotal studies: TRUST-I (NCT04395677) in China, and TRUST-II (NCT04919811), a global study. Based on the integrated analysis of the TRUST-I and TRUST-II clinical studies, an NDA has been submitted for taletrectinib to the U.S. FDA for the treatment of patients with locally advanced or metastatic ROS1-positive NSCLC. Citation Format: Hitisha K. Patel, Laura Heller, Kevin Bowman, Zheyi Hu, Yan Zhang, Irma M. Grossi, Max Pan, Gary Hattersley. Taletrectinib, a next generation selective ROS1 inhibitor, inhibits growth of ROS1 wild-type and ROS1-G2032R xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5612.