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|Ref Type||Journal Article|
|Authors||Papadopoulos KP, Borazanci E, Shaw AT, Katayama R, Shimizu Y, Zhu VW, Sun TY, Wakelee HA, Madison R, Schrock AB, Senaldi G, Nakao N, Hanzawa H, Tachibana M, Isoyama T, Nakamaru K, Deng C, Li M, Fan F, Zhao Q, Gao Y, Seto T, Jänne PA, Ou SI|
|Title||U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 Jun 26|
|Abstract Text||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 ≥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.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 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.Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Taletrectinib||DS6051b|DS-6051B|DS-6051|AB-106||ROS1 Inhibitor 19 Trk Receptor Inhibitor (Pan) 29||Taletrectinib (DS6051b) is an inhibitor of NTRK1/2/3 and ROS1 fusion proteins, which blocks downstream signaling and may lead to inhibition of tumor cell growth (PMID: 32591465).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|ROS1||L2086F||missense||unknown||ROS1 L2086F lies within the protein kinase domain of the Ros1 protein (UniProt.org). L2086F confers resistance to ROS1 inhibitors in the context of ROS1 fusion (PMID: 32591465), but has not been biochemically characterized and therefore, its effect on Ros1 protein function is unknown (PubMed, Mar 2022).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ROS1 rearrange||lung non-small cell carcinoma||predicted - sensitive||Taletrectinib||Phase I||Actionable||In a Phase I trial, Taletrectinib (DS6051b) demonstrated manageable toxicity, resulted in an objective response rate of 33.3% (2/6) in patients with advanced non-small cell lung cancer harboring ROS1 rearrangements (PMID: 32591465).||32591465|