U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors

Clin Cancer Res. 2020 Sep 15;26(18):4785-4794. doi: 10.1158/1078-0432.CCR-20-1630. Epub 2020 Jun 26.


Purpose: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib.

Patients and methods: 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 (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity.

Results: A total of 46 patients were enrolled. Steady-state peak concentration (C max) and exposure (AUC0-8) increased dose dependently from 50-mg to 800-mg once-daily 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 two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1+ NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation.

Conclusions: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Food-Drug Interactions*
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / adverse effects*
  • Imidazoles / pharmacokinetics
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms / diagnosis
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Pyridazines / administration & dosage
  • Pyridazines / adverse effects*
  • Pyridazines / pharmacokinetics
  • Receptor, trkA / antagonists & inhibitors
  • Response Evaluation Criteria in Solid Tumors
  • Young Adult


  • Imidazoles
  • NTRK1 protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyridazines
  • Protein-Tyrosine Kinases
  • ROS1 protein, human
  • Receptor, trkA
  • taletrectinib