FDA Approves Repotrectinib in NTRK-Positive Solid Tumors

3D rendering of tumor cell: ©nevio - stock.adobe.com

• The FDA has granted accelerated approved repotrectinib (Augtyro) for the treatment of adult and pediatric patients aged 12 or older with locally advanced or metastatic solid tumors that harbor an NTRK gene fusion.
• The approval is supported by findings from the registrational phase 1/2 TRIDENT-1 study (NCT03093116).
• Repotrectinib is also approved for the treatment of ROS1-positive non–small cell lung cancer (NSCLC).

Repotrectinib is now an FDA-approved therapy for patients with NTRK-positive locally advanced or metastatic solid tumors where surgical resection is likely to result in severe morbidity.¹

“While great advancements have been made over the last decade, patients with NTRK-positive locally advanced or metastatic solid tumors still experience significant unmet needs. New and effective treatment options that may improve durability of response and address resistance to existing tyrosine kinase inhibitors are critical to helping patients with these aggressive tumors,” said Joseph Fiore, vice president, global program lead, Bristol Myers Squibb, in a press release.²

In February 2024, the FDA granted the supplemental new drug application of repotrectinib priority review. Repotrectinib was approved for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC in November 2023.

“What's different about repotrectinib, what makes it more appealing or possibly a best in class, is actually the way the drug has been restructured or designed to overcome some of the acquired resistance mutations, which translates into a better durability of response. Also, it had excellent CNS penetration, as we've seen now with the TRIDENT-1 study,” Firas B. Badin, MD, the medical director of oncology research at the Baptist Health Medical Group in Lexington, Kentucky, told Targeted Oncology^TM in an interview.

In TRIDENT-1, patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions were enrolled and treated with 160 mg of repotrectinib once daily for 14 days followed by 160 mg of repotrectinib twice daily. The study’s primary end point was overall response rate (ORR) using RECIST v1.1 criteria, and secondary end points included duration of response (DOR), clinical benefit rate, time to response, and ORR among tyrosine kinase inhibitor (TKI)-pretreated patients with ROS1 G2032R.

Findings showed that patients treated with repotrectinib who were TKI-naive and TKI-pretreated, including patients who had ROS1 resistance mutations, there was a confirmed ORR of 58% (95% CI, 41%-73%) and 50% (95% CI, 35%-65%). The median DOR was not estimable (NE; 95% CI, NE-NE) in patients naïve to tyrosine kinase inhibitors vs 9.9 months (95% CI, 7.4-13.0) in those pretreated with the therapy.

The most common treatment-emergent adverse event (TEAE) was dizziness (61.3%), which was grade 1 in 73.2% of patients. A total of 19.6% of patients had ataxia, with 20 patients (4.5%) reporting ataxia in the absence of dizziness, and 45% of patients had TEAEs leading to drug interruption, 34% leading to dose reductions, and 9.7% leading to drug discontinuation.

REFERENCES:

1. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. News release. FDA. June 13, 2024. Accessed June 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-repotrectinib-adult-and-pediatric-patients-ntrk-gene-fusion-positive

2. U.S. Food and Drug Administration accepts for priority review Bristol Myers Squibb’s Application for Augtyro™ (repotrectinib) for the treatment of patients with NTRK-positive locally advanced or metastatic solid tumors. News release. Bristol Myers Squibb. February 14, 2024. Accessed April 19, 2024. https://tinyurl.com/3yzhnenc

3. U.S. Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for repotrectinib for the treatment of patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer. News release. Bristol Myers Squibb. May 30, 2023. Accessed April 19, 2024. http://tinyurl.com/bdeabb6d

4. Cho BC, Lin JJ, Camidge DR, et al. Pivotal topline data from the phase 1/2 TRIDENT-1 trial of repotrectinib in patients with ROS1+ advanced non-small cell lung cancer (NSCLC). Presented at: EORTCNCI-AACR Molecular Targets and Cancer Therapeutics Symposium; http://bit.ly/3t92SyE