FDA Accepts sNDA of Repotrectinib for Solid Tumors With NTRK Alterations

• The FDA has accepted the supplemental new drug application (sNDA) for repotrectinib (Augtyro) for the treatment of patients aged 12 and older with solid tumors harboring an NTRK gene fusion.
• The decision is based on data from the phase 1/2 TRIDENT-1 trial (NCT03093116) in adult patients and the CARE study (NCT04094610) in pediatric patients, both of which evaluated repotrectinib in NTRK-positive solid tumors.
• The FDA has set a Prescription Drug User Fee Act (PDUFA) date for the agent of June 15, 2024.

The sNDA for repotrectinib has been accepted by the FDA for the treatment of patients aged 12 and older with solid tumors that have an NTRK gene fusion and are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, according to Bristol Myers Squibb.¹

This regulatory decision is supported by findings from the registrational phase 1/2 TRIDENT-1 trial which evaluated the agent in adult patients with NTRK-positive solid tumors and the CARE study of repotrectinib for the treatment of pediatric patients with NTRK-positive solid tumors. In both studies, repotrectinib led to clinically meaningful response rates among patients with locally advanced or metastatic solid tumors harboring NTRK gene fusions. The safety profile of the agent was also well-tolerated and adverse effects (AEs) were manageable.

Priority review status has also been granted to the sNDA. The PDUFA date has been set for June 15, 2024.

“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.

Repotrectinib is a next-generation tyrosine kinase inhibitor (TKI) which aims to target locally advanced or metastatic solid tumors that are ROS1-positive or NTRK-positive. In November 2023, the FDA approved repotrectinib for adult patients with locally advanced or metastatic ROS1-positive NSCLC, also based on data from TRIDENT-1.

“We look forward to working closely with the FDA on the review of our application for [repotrectinib] for this tumor-agnostic indication and potentially offering patients with NTRK-positive disease a new, durable treatment option,” added Fiore.

3D illustration of llung with cancer cells: © catalin - stock.adobe.com

TRIDENT-1

In the phase 1/2 TRIDENT-1 study, 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 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 (CBR), time to response (TTR), and ORR among TKI-pretreated patients harboring ROS1 G2032R.

Findings showed that those treated with repotrectinib who were TKI-naive and TKI-pretreated, including patients who had ROS1 resistance mutations, yielded high response rates and a clinically meaningful DOR.^2,3 The 12-month landmark DOR was 86.1% after a median follow-up of 18.1 months for the TKI-naive patients, and the ORR was 78.9% (95% CI, 67.6%-87.7%). Patients previously treated with 1 prior ROS1 TKI and no prior chemotherapy had an ORR of 37.5% (95% CI, 24.9%-51.5%) with a 6-month landmark DOR of 79.5% after 15.5 months median follow-up.²

Among all patients treated with repotrectinib (n = 71), the median DOR was 13.3 months (range, 0.80-60.6+). Fifty-six patients achieved a complete response of whom the median duration of treatment was 15.5 months (range, 3.1-60.6+). There was also activity seen in pretreated patients with ROS1 G032R resistance mutation, according to investigators, with an ORR of 58.5% (95% CI, 32.9-81.6).

Regarding safety, the most common treatment-emergent AE (TEAE) was low-grade dizziness (61.3%). This 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% had TEAEs leading to dose reductions, and 9.7% had TEAEs leading to drug discontinuation.

CARE Study

The phase 1/2 open-label CARE study is also evaluating repotrectinib for the treatment of pediatric and young adult patients with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK alterations.⁴ Phase 1 of the study aims to find the highest dose of the repotrectinib that can be given in this patient population and phase 2 will evaluate the efficacy of repotrectinib.

Enrollment is open to patients 12-25 years of age with ALK, ROS1, or NTRK alterations who have cancer that has continued to grow despite standard therapy or for which no standard therapy exists. Patients must recover from any AEs from prior therapies before study entry.

The primary end points are to determine the dose-limiting toxicities, find the pediatric recommended phase 2 dose, and evaluate ORR. Secondary end points include ORR, CBR, TTR, DOR, intracranial ORR, central nervous system progression-free survival (PFS), PFS, OS, and pharmacokinetics.

REFERENCES:

1. 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 February 14, 2024. http://tinyurl.com/2hdum5p9

2. 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 February 14, 2024. http://tinyurl.com/bdeabb6d

3. 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

4. A study of repotrectinib in pediatric and young adult subjects harboring ALK, ROS1, OR NTRK1-3 alterations. ClinicalTrials.gov. Updated January 24, 2024. Accessed February 14, 2024. https://clinicaltrials.gov/study/NCT04094610