US phase 1 first-in-human study of taletrectinib (DS-6051b/AB-106), a ROS1/TRK inhibitor, in patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research Papadopoulos, K. P., Borazanci, E. n., Shaw, A. T., Katayama, R. n., Shimizu, Y. n., Zhu, V. W., Sun, T. Y., Wakelee, H. A., Madison, R. n., Schrock, A. B., Senaldi, G. n., Nakao, N. n., Hanzawa, H. n., Masaya, T. n., Isoyama, T. n., Nakamaru, K. n., Deng, C. n., Li, M. n., Fran, F. n., Zhao, Q. n., Gao, Y. n., Seto, T. n., Janne, P. A., Ou, S. I. 2020


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