NDA Accepted in China for Zurletrectinib for NTRK Gene Fusion+ Advanced Solid Tumors

Image Credit:©Sebastian Kaulitzki – stock.adobe.com

The Center for Drug Evaluation of China’s National Medical Products Administration has accepted a new drug application for the new-generation pan-TRK inhibitor zurletrectinib (ICP-723) for the treatment of adult and adolescent patients at least 12 years of age with advanced solid tumors harboring NTRK gene fusions.1

The registrational trial investigating zurletrectinib in this patient population showed that the agent was effective and had a good safety profile, according to a news release. The trial also demonstrated the agent’s ability to overcome acquired resistance to first-generation TRK inhibitors. Previously reported data from the trial showed an overall response rate between 80% and 90% in adult patients with various NTRK gene fusion–positive cancers who received zurletrectinib at a dose of at least 8 mg.2

The registrational trial is also being accelerated to include pediatric patients between 2 and 12 years of age. InnoCare Pharma received approval to conduct this trial in pediatric patients in China in July 2023, and the first pediatric patient was dosed in January 2024.2,3

“Zurletrectinib has demonstrated outstanding efficacy and safety [profiles] in adult, adolescent, and pediatric patients with tumors harboring NTRK fusion genes, bringing better treatment options for patients with solid tumors,” Jasmine Cui, PhD, the co-founder, chairwoman and chief executive officer of InnoCare, stated in the news release. “The Company is expanding the scope of its solid tumor pipelines through a combination of targeted therapies, immune-oncology approaches, and cutting-edge antibody-drug conjugate technology, looking forward to meeting the unmet needs of patients with solid tumors early.”

Authors of a preclinical study published in the British Journal of Cancer in June 2024 note that among many patients with NTRK fusion–positive cancers, resistance to first-generation TRK inhibitors—typically mediated by acquired NTRK mutations—is common.4 Although next-generation TRK inhibitors, such as repotrectinib (Augtyro) and selitrectinib (BAY 2731954; LOXO-195), are active against TRK-mutant disease, the treatment paradigm lacks novel, potent, and specific next-generation TRK inhibitors. Thus, investigators evaluated the activity of zurletrectinib on in vitro and in vivo models of NTRK fusion–positive and TRK wild-type models.

Molecular docking showed that similarly to other type I TRK inhibitors, zurletrectinib occupies the ATP binding pocket of TRK kinases and interacts with key gatekeeper and xDFG position residues. However, unlike other TRK inhibitors that are approved or in clinical development, zurletrectinib’s fluoropyrrolidine moiety allows the drug to uniquely interact with the D668 and K544 residues of TRKA, which suggests that zurletrectinib is highly selective for TRK kinases. Furthermore, in vitro kinase assays demonstrated that zurletrectinib exhibited similar inhibitions of growth and TRK-mediated signaling of NTRK fusion–positive primary human cancer cell lines compared with selitrectinib and repotrectinib.

In vitro assays also demonstrated that zurletrectinib maintains activity against first-generation, on-target TRK inhibitor mutations that are acquired upon progression on first-generation TRK inhibitors. Consistent findings were observed in primary human NTRK fusion–positive cell lines, where zurletrectinib, selitrectinib, and repotrectinib all inhibited the growth and TRKA-mediated signaling of lines of the TRKA G595R mutation. However, the potency of these agents against the TRKA G595R/G667C compound mutation was significantly reduced. Furthermore, cell viability assays performed on mouse Ba/F3 cells that were transduced to express a range of first-generation TRK inhibitor resistance mutations showed that zurletrectinib had the strongest next-generation TRK inhibition activity vs selitrectinib and repotrectinib.

In vivo assays confirmed the potency and activity of zurletrectinib and showed that no weight loss occurred with twice-daily, 1-mg/kg oral administration, indicating that the agent was well tolerated. Moreover, at 2 hours post-administration in male Sprague Dawley rats, zurletrectinib demonstrated superior brain penetration compared with selitrectinib, and repotrectinib, at 15.5% vs 10.2% and 6.17%, respectively. Zurletrectinib treatment was also associated with increased brain/plasma ratios over time and the highest cerebrospinal fluid/plasma ratio.

References

1. InnoCare announces the acceptance of new drug application for pan-TRK inhibitor zurletrectinib in China. News release. InnoCare Pharma. April 16, 2025. Accessed April 16, 2025. https://www.innocarepharma.com/m/en/news/activity/en020250416
2. InnoCare announces first pediatric patient dosed in clinical trial of pan–TRK inhibitor zurletrectinib in China. News release. InnoCare Pharma. January 24, 2024. Accessed April 16, 2025. https://www.innocarepharma.com/m/en/news/activity/en020240124
3. InnoCare announces approval of clinical trial of pan–TRK inhibitor zurletrectinib for the treatment of pediatric patients in China. News release. InnoCare Pharma. July 26, 2023. Accessed April 16, 2025. https://www.innocarepharma.com/m/en/news/activity/en020230726
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