Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent pre-clinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human US-phase 1 results of taletrectinib.Patients =18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1200 mg once daily [QD] or 400 mg twice daily). Primary objectives were safety/tolerability, and maximum tolerated dose (MTD) determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity.A total of 46 patients were enrolled. Steady-state peak concentration (Cmax) and exposure (AUC0-8) increased dose dependently from 50 mg to 800 mg QD doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval: 104% - 149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in 2 patients (1200 mg QD dose). MTD was 800 mg QD. Most common treatment-related adverse events (TRAEs) were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800 mg QD-dose cohort. Confirmed ORR was 33.3% among the 6 RECIST-evaluable crizotinib-refractory ROS1+ NSCLC patients. One TPM3-NTRK1 differentiated thyroid cancer patient achieving a confirmed partial response (PR) of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation.Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in crizotinib-refractory ROS1+ NSCLC patients.
View details for DOI 10.1158/1078-0432.CCR-20-1630
View details for PubMedID 32591465