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- W4361947496 abstract "<div>AbstractPurpose:<p>Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against <i>ROS1</i> G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib.</p>Patients and Methods:<p>Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring <i>ROS1</i>/<i>NTRK</i> 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.</p>Results:<p>A total of 46 patients were enrolled. Steady-state peak concentration (<i>C</i><sub>max</sub>) and exposure (AUC<sub>0-8</sub>) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC<sub>0-24</sub> 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 <i>ROS1<sup>+</sup></i> NSCLC. One patient with <i>TPM3-NTRK1</i> differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive <i>ROS1</i> L2086F as an acquired taletrectinib-resistance mutation.</p>Conclusions:<p>Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory <i>ROS1<sup>+</sup></i> NSCLC.</p></div>" @default.
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- W4361947496 date "2023-03-31" @default.
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- W4361947496 title "Data from U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors" @default.
- W4361947496 doi "https://doi.org/10.1158/1078-0432.c.6529236" @default.
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