Taletrectinib Shows Preliminary Efficacy in Crizotinib-Refractory ROS1+ NSCLC

"Taletrectinib is a promising oral tyrosine kinase inhibitor highly selective for ROS1/NTRK mutations with potent activity against ROS1 resistance mutations like G2032R."

Taletrectinib (DS-6051b/AB-106) showed preliminary efficacy and manageable toxicities at the maximum tolerated dose (MTD) in a phase 1 trial of patients with advanced solid tumors.1

“Taletrectinib is a promising oral tyrosine kinase inhibitor highly selective for ROS1/NTRK mutations with potent activity against ROS1 resistance mutations like G2032R,” Sai-Hong Ignatius Ou, MD, PhD, the corresponding author of the paper from University of California Irvine School of Medicine, said in a statement. “The drug had manageable toxicities at the MTD of 800 mg daily and showed preliminary efficacy in crizotinib-refractory ROS1 positive NSCLC patients.”

For 6 of the patients with non-small cell lung cancer (NSCLC) who were RECIST-evaluable, crizotinib (Xalkori)-refractory, and ROS1-positive, there was a confirmed overall response rate of 33.3%. One patient with TPM3-NTRK1 differentiated thyroid cancer achieved a confirmed partial response of 27 months by the time of the data cutoff. The investigators identified an acquired taletrectinib-resistance mutation—a cabozantinib-sensitive ROS1 L2086F.

There was a steady-state peak concentration and exposure for 46 patients enrolled in the trial, which was increased dose-dependently from 50 mg to 800 mg daily doses of taletrectinib. There was a 123% (90% CI, 104%-149%) ratio of the geometric mean of AUC024 between patients who were low-fat-diet-fed and those in a fasted state.

Two patients had dose-limiting toxicities of grade 3 transaminases increase. The most common treatment-related adverse events were nausea at 47.8%, diarrhea at 43.5%, and vomiting at 32.6%. There were pain score reductions observed in the 800 mg daily-dose cohort.

“We are honored to have our study selected for publication in Clinical Cancer Research. There is a significant unmet need for next generation tyrosine kinase inhibitors to overcome resistance that develops to existing agents like crizotinib, and we are highly focused on developing taletrectinib for both first, and second-line use in global markets,” Bing Yan, MD, MBA, chief medical officer and founder of AnHeart, said in a press release. “We are steadily making progress towards launching our Phase 2 trials [NCT04395677] in first-and second-line NSCLC patients with ROS1 mutations in the next few weeks.”

In this study, patients who were 18 years or older with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. There was accelerated titration followed by modified continuous reassessment method and escalation with overdose control used for these patients. The doses of taletrectinib ranged from 50 mg to 1200 mg once daily or 400 mg twice daily.

The primary end points of the trial were safety/tolerability and MTD determination. Secondary end points included food-effect pharmacokinetics and antitumor activity.

These data were supported by AnHeart Therapeutics, Co., Ltd., a clinical stage biopharmaceutical oncology company which is focused on developing novel agents for patients who are underserved in global markets.2


1. Papadopoulos KP, Borazanci E, Shaw AT, et al. US phase 1 first-in-human study of taletrectinib (DS-6051b/AB-106), a ROS1/TRK inhibitor, in patients with advanced solid tumors. Clin Cancer Res. Published OnlineFirst June 26, 2020. doi:10.1158/1078-0432.CCR-20-1630

2. AnHeart Therapeutics Announces Acceptance of Taletrectinib Phase 1 Data for Publication in Clinical Cancer Research [press release]. GlobeNewswire. Published June 26, 2020. Accessed June 26, 2020. https://bit.ly/31k0Lv6