WCLC 2025 - Posters & ePosters-P3.12.12 Clinical Pharmacologic Characteristics of Taletrectinib

Pdf Summary

Taletrectinib is an oral, potent, CNS-active, selective next-generation ROS1 inhibitor approved in China and the US for treating adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). Data from two Phase 2 studies, TRUST-I and TRUST-II, demonstrated its robust, durable efficacy and favorable safety profile.<br /><br />The clinical pharmacologic properties of taletrectinib were evaluated across 10 Phase 1 and 2 studies involving both healthy participants and cancer patients, assessing absorption, metabolism, elimination, repeat-dose pharmacokinetics (PK), and drug–drug interactions (DDIs). Taletrectinib exhibits dose-proportional PK over a 50–1200 mg once-daily (QD) range, with rapid oral absorption (median tmax 2–6 hours), steady state by Day 8, and a long terminal half-life (~80–100 hours in healthy adults), supporting once-daily dosing. The drug displays wide tissue distribution and concentration-dependent plasma protein binding.<br /><br />Metabolism predominantly occurs via CYP3A4 enzymes, as confirmed by in vitro studies and clinical mass balance data showing 80% absorption with primarily hepatic elimination (75% feces, 11% urine). Taletrectinib can inhibit CYP3A4, CYP2D6, CYP2C8, and various transporters and induce CYP1A2 and CYP3A, implicating potential DDIs.<br /><br />Clinical DDI studies indicated that coadministration with itraconazole (strong CYP3A4 inhibitor) significantly increases taletrectinib exposure, while rifampin (strong CYP3A4 inducer) decreases it. Proton pump inhibitor omeprazole reduces taletrectinib absorption due to its pH-dependent solubility. Taletrectinib showed no significant effect on P-gp substrate digoxin PK.<br /><br />Population PK analyses revealed no clinically meaningful differences in taletrectinib exposure based on age, sex, weight, mild hepatic impairment, or mild-to-moderate renal impairment.<br /><br />In summary, taletrectinib has predictable, dose-proportional pharmacokinetics with wide tissue penetration and a long half-life enabling convenient once-daily dosing. CYP3A4 modulators and proton pump inhibitors can affect its exposure and should be considered during clinical use.

Asset Subtitle

Lyudmila Bazhenova

Meta Tag

Speaker Lyudmila Bazhenova

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

Taletrectinib

ROS1 inhibitor

non-small cell lung cancer

pharmacokinetics

CYP3A4 metabolism

drug-drug interactions

phase 2 clinical trials

oral absorption

proton pump inhibitors

once-daily dosing