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

Abstract

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.

• Authors: Kyriakos P Papadopoulos, Erkut Borazanci, Alice T Shaw, Ryohei Katayama, Yuki Shimizu, Viola W Zhu, Thomas Yang Sun, Heather A Wakelee, Russell Madison, Alexa B Schrock, Giorgio Senaldi, Naoki Nakao, Hiroyuki Hanzawa, Masaya Tachibana, Takeshi Isoyama, Kenji Nakamaru, Chenhui Deng, Meijing Li, Frank Fan, Qinying Zhao, Yanfei Gao, Takashi Seto, Pasi A Jänne, Sai-Hong Ignatius Ou
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 18 Pg. 4785-4794 (09 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32591465 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

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

Topics

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