Zurletrectinib: Advanced TRK Inhibitor Effective Against NTRK Fusion-Positive Tumors with On-Target Resistance

In a significant development in the field of cancer treatment, InnoCare has announced that a paper in the prestigious British Journal of Cancer, a part of the Nature journal series, has highlighted the effectiveness of zurletrectinib. The study, titled "Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumors with on-target resistance to first-generation agents," showcases zurletrectinib as a potent, next-generation TRK inhibitor with superior abilities compared to its predecessors.

Zurletrectinib has demonstrated a high level of efficacy against TRKA, TRKB, and TRKC WT kinases, in addition to acquired resistance mutations such as TRKA G595R and TRKA G667C. Compared to both first-generation TRK inhibitors like larotrectinib and next-generation inhibitors such as selitrectinib and repotrectinib, zurletrectinib has shown significantly higher activity against most TRK inhibitor resistance mutations. In xenograft models derived from NTRK fusion-positive cells, zurletrectinib (1 mg/kg BID) was able to inhibit tumor growth at doses 30 times lower than those needed for selitrectinib.

Importantly, zurletrectinib has shown improved ability to cross the blood-brain barrier in pharmacokinetic studies conducted on SD rats. This enhanced brain penetration was not only superior to selitrectinib and repotrectinib but also translated into better antitumor efficacy. In an orthotopic mouse glioma xenograft model harboring the TRKA G598R/G670A resistance mutation, zurletrectinib (15 mg/kg) significantly extended the survival of mice with orthotopic NTRK fusion-positive, TRK-mutant gliomas. The median survival for mice treated with zurletrectinib was 104 days, compared to 66.5 days for repotrectinib and 41.5 days for selitrectinib, demonstrating statistically significant superior efficacy (P < 0.05). The treatment also exhibited an excellent safety profile.

The research was authored by notable experts in the field, including Dr. Alexander Drilon from Memorial Sloan Kettering Cancer Center in New York and Dr. Emiliano Cocco from the University of Miami's Miller School of Medicine. Paolo Roa, also from the University of Miami, served as the first author of the paper.

InnoCare is propelling the registrational trial of zurletrectinib forward in China. The clinical studies encompass NTRK fusion patients across different age groups, including adults, adolescents, and pediatric patients. Zurletrectinib has consistently demonstrated good efficacy and a favorable safety profile, addressing acquired resistance to first-generation TRK inhibitors and providing benefits to patients who have not responded to previous TRK inhibitor therapies.

InnoCare is a commercial-stage biopharmaceutical company dedicated to creating breakthrough drugs for cancer and autoimmune diseases that address unmet medical needs, both in China and globally. The company is listed on the Hong Kong Stock Exchange (HKEX: 09969) and the Shanghai Stock Exchange (SSE: 688428) and has operational branches in Beijing, Nanjing, Shanghai, Guangzhou, Hong Kong, and the United States.

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