WCLC 2025 - Posters & ePosters-P3.12.04 Taletrectinib, a Next Generation Selective ROS1 Inhibitor, Exhibits a Differentiated Profile in ROS1 Fusion Models

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This poster presents preclinical data on taletrectinib, a next-generation, CNS-active selective ROS1 inhibitor developed for treating ROS1-positive non–small cell lung cancer (NSCLC). ROS1 gene fusions occur in ~2% of NSCLC patients and cause constitutive ROS1 activation. Existing FDA-approved ROS1 TKIs—crizotinib, entrectinib, and repotrectinib—have limitations: crizotinib and entrectinib are weak against common resistance mutations such as ROS1G2032R, while repotrectinib, despite CNS activity, causes high neurological adverse events due to TRKB inhibition.<br /><br />Taletrectinib exhibits potent biochemical inhibition of both wild-type ROS1 (ROS1WT) and the ROS1G2032R resistance mutation at clinically relevant concentrations, with improved selectivity sparing TRKB (linked to CNS toxicity). In contrast, crizotinib and entrectinib lacked activity against ROS1G2032R, and repotrectinib showed less selectivity over TRKB.<br /><br />Cellular and animal model studies demonstrated taletrectinib’s broad efficacy against various fusion partners and ROS1 resistance mutations, causing tumor regression and inhibiting ROS1 phosphorylation across models. Importantly, taletrectinib prevented emergence of resistant clones in ROS1WT fusion-positive cells, unlike crizotinib and entrectinib, which led to resistant clones.<br /><br />In intracranial patient-derived xenograft (PDX) mice with SDC4-ROS1 fusion, taletrectinib prolonged survival over 100 days, showing CNS penetration and therapeutic potential. Pharmacodynamic data indicate taletrectinib maintains high target coverage at clinically achievable exposures.<br /><br />Overall, taletrectinib offers a differentiated therapeutic profile: effective inhibition of ROS1WT and key resistance mutations, CNS activity, and lower risk of neurotoxicity. These properties address unmet needs in ROS1 NSCLC treatment, particularly overcoming resistance mutations and improving tolerability compared to current ROS1 TKIs. Taletrectinib is currently approved for advanced ROS1 NSCLC in China and the US, supported by ongoing clinical trials demonstrating robust response rates, intracranial activity, and prolonged progression-free survival.

Asset Subtitle

Hitisha Patel

Meta Tag

Speaker Hitisha Patel

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

taletrectinib

ROS1-positive non–small cell lung cancer

ROS1G2032R resistance mutation

CNS-active ROS1 inhibitor

ROS1 tyrosine kinase inhibitors

crizotinib

entrectinib

repotrectinib

intracranial patient-derived xenograft model

ROS1 resistance mutation inhibition