Reference Detail

Ref Type

Journal Article

PMID

(32591465)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2020 Jun 26	4785-4794	Clin Cancer Res

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Taletrectinib	Taletrectinib	6	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Taletrectinib		DS6051b\|DS-6051B\|DS-6051\|AB-106	ROS1 Inhibitor 20 Trk Receptor Inhibitor (Pan) 32	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, Apr 2024).	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