Zurletrectinib Receives Priority Review from NMPA for NTRK Gene Fusion+ Advanced Solid Tumors

Zurletrectinib for NTRK Gene Fusion+

Advanced Solid Tumors | Image Credit:

© Sebastian Kaulitzki – stock.adobe.com

The pan-TRK inhibitor zurletrectinib (ICP-723) has received priority review from China’s Center for Drug Evaluation of the National Medicinal Products Administration (NMPA) for the treatment of patients with advanced solid tumors harboring NTRK gene fusions.1

In April 2025, a new drug application seeking the approval of the pan-TRK inhibitor for this indication in adult and adolescent patients at least 12 years of age was accepted by the NMPA after data from a registrational trial demonstrated that the agent was effective and had a good safety profile.2 Notably, previously reported data from the trial had revealed that zurletrectinib at a dose of 8 mg or higher demonstrated an overall response rate (ORR) between 80% and 90% in adult patients with multiple NTRK gene fusion–positive cancers.3 Following these positive data, the first pediatric patient was dosed with the agent in January 2024.

“We are delighted that zurletrectinib has been granted priority review. Zurletrectinib has demonstrated outstanding efficacy and [has] a favorable safety profile,” Jasmine Cui, PhD, co-founder, chairwoman, and chief executive officer of InnoCare—the developer of zurletrectinib, said in a news release.1 “We anticipate it will provide better treatment options for eligible patients with solid tumors earlier.”

A preclinical study published in the British Journal of Cancer in June 2024 evaluated zurletrectinib as a next-generation TRK inhibitor for the treatment of patients with NTRK fusion–positive tumors. Findings from the study demonstrated that the agent is a highly potent therapy with stronger in vivo brain penetration and intracranial activity compared with other next-generation agents.4 Specifically, zurletrectinib was shown to be more active than other TRK inhibitors, including larotrectinib (Vitrakvi), selitrectinib (BAY2731954), and repotrectinib (Augtyro), although it demonstrated similar potency as these agents against TRKA, TRKB, and TRKC wild-typekinases.

Furthermore, zurletrectinib demonstrated inhibition against tumor growth in vivo in subcutaneous xenograft models that were derived from NTRK fusion–positive cells with a dose 30 times lower than that of selitrectinib. Of note, zurletrectinib demonstrated increased brain penetration in rats at 0.5 hours and 2 hours after single oral administration compared with selitrectinib and repotrectinib treatment. The brain penetration capacities of zurletrectinib, selitrectinib, and repotrectinib were assessed after rats received the treatments at single oral doses of 10 mg/kg. At 2 hours following treatment, all 3 agents reached the absorption peak. Particularly, 2 hours after administration, zurletrectinib demonstrated increased brain penetration vs repotrectinib and selitrectinib; the brain/plasma ratios with each of these agents were 15.5%, 10.2%, and 6.17%, respectively. Moreover, the brain/plasma ratio of zurletrectinib increased from 7.17% at 0.5 hours to 15.5% at 2 hours.

The association between zurletrectinib and increased brain penetration in brain tumors was evaluated and tested in vivo among mouse glioma orthotopic xenografts harboring TRKA G598 or TRKA G598R/G670A mutations. One week following intracranial tumor implantation, the mice were randomly assigned to receive larotrectinib at 30 mg/kg twice daily, selitrectinib at 30 mg/kg twice daily, repotrectinib at 15 mg/kg twice daily, or zurletrectinib at 15 mg/kg twice daily. The mice were monitored and weighed 2 times a week for signs of tumor-related discomfort, survival, and toxicity. Zurletrectinib significantly improved the survival of the mice; the median survival durations were 41.5 days, 66.5 days, and 104 days for selitrectinib, repotrectinib, and zurletrectinib, respectively (P < .05). After monitoring, there were no differences in the weights of mice from among the 4 arms, which suggested that the respective treatments were well tolerated, although some mice received treatment for longer than 150 days.

References

1. InnoCare’s zurletrectinib receives priority review from China’s NMPA. News release. May 2, 2025. Accessed May 2, 2025. https://www.innocarepharma.com/en/news/activity/en020250502-Zurletrectinib-Receives-Priority-Review-from-NMPA
2. InnoCare announces the acceptance of new drug application for pan-TRK inhibitor zurletrectinib in China. News release. InnoCare Pharma. April 16, 2025. Accessed May 2, 2025. https://www.innocarepharma.com/m/en/news/activity/en020250416
3. InnoCare announces first pediatric patient dosed in clinical trial of pan-TRK inhibitor zurletrectinib in China. News release. InnoCare Pharma. January 23, 2024. Accessed May 2, 2025. https://www.innocarepharma.com/en/news/activity/en020240124
4. Roa P, Foglizzo V, Harada G, et al. Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents. Br J Cancer. 2024;131(3):601-610. doi:10.1038/s41416-024-02760-1