FDA Grants Priority Review to Repotrectinib for NTRK+ Solid Tumors

February 14, 2024

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Repotrectinib is under priority review for patients with NTRK-positive locally advanced or metastatic solid tumors and high unmet medical need.

US FDA

The FDA has accepted and granted priority review to thesupplemental New Drug Application for the next-generation TKI repotrectinib (Augtyro)in the treatment of adult and pediatric patients 12 years of age and older with NTRK-positive, locally advanced or metastatic solid tumors for whom surgical resection is likely to result in severe morbidity, according to a press release from Bristol Myers Squibb.¹

This regulatory decision is based on results from the registrational phase 1/2 TRIDENT-1 (NCT03093116) and the phase 1/2 CARE (NCT04094610) trials, in which repotrectinib produced clinically meaningful and durable responses in adult or pediatric patients with NTRK-positive solid tumors, respectively. Notably, both patient subsets experienced intracranial responses, as did patients with tumors expressing common resistance mutations. Repotrectinib was also proven to be well tolerated with a generable manageable safety profile.

The FDA has assigned the agent a Prescription Drug User Fee Act (PDUFA) goal date of 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,” Joseph Fiore, vice president and global program lead for Augtyro at Bristol Myers Squibb, stated in the news release. “New and effective treatment options that may improve durability of response and address resistance to existing TKIs are critical to helping patients with these aggressive tumors.”

Repotrectinib was previously approved by the FDA in November, 2023, for the treatment of adult patients with locally advanced or metastatic ROS1-positive non—small cell lung cancer (NSCLC) based on data from TRIDENT-1.²

Additionally, the European Medicines Agency validated the marketing authorization application for repotrectinib in January, 2024 for both ROS1 TKI-naive and -exposed adult patients with ROS1-positive locally advanced or metastatic NSCLC, as well as TKI-naïve and -exposed adult and pediatric patients with NTRK-positive locally advanced or metastatic solid tumors.³

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

TRIDENT-1 Trial

TRIDENT-1 is a multicenter, single-arm, open-label study of patients with locally advanced or metastatic NSCLC harboring ROS1 fusions.1,4 Eligible patients needed to have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Patients with a history of interstitial lung disease, drug-associated pneumonitis, prolonged QTc interval, or significant, uncontrolled, or active cardiovascular disease were excluded from the study. Efficacy assessment was conducted in participants with at least 8 months of follow-up since their first dose, excluding those with symptomatic brain metastases.

Treatment consisted of 160 mg of repotrectinib once daily for 2 weeks, followed by 160 mg twice daily until disease progression or intolerable toxicity. The primary end point in phase 2 is overall response rate (ORR), with key secondary end points including duration of response (DOR) assessed by blinded independent central review (BICR) and RECIST v1.1 criteria, progression-free survival (PFS), and intracranial responses in 6 expansion cohorts.

Patients without prior exposure to ROS1 TKIs but who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy (n = 71), and those previously treated with a ROS1 TKI but without prior exposure to platinum-based chemotherapy or immunotherapy (n = 56) were included in the efficacy population.

In the ROS1 TKI–naive cohort, the median DOR was 34.1 months (95% CI, 25.6-not evaluable [NE]), with 70% of patients responding for at least 12 months, and the ORR was 79% (95% CI, 68%-88%). Intracranial responses were seen in 7 of 8 patients who had measurable central nervous system (CNS) metastases at baseline. In the ROS1 TKI–exposed cohort, the ORR was 38% (95% CI, 25%-52%), the median DOR was 14.8 months (95% CI, 7.6-NE), with 48% of patients responding for 12 months or longer, and 5 out of 12 patients with baseline measurable CNS metastases achieved intracranial responses.

Serious adverse effects (AEs) occurred in 33% of patients, and 4.2% of patients experienced fatal AEs. AEs that led to permanent discontinuation (8%) included dyspnea, pneumonitis, and muscular weakness. Dose interruptions and reductions were required for 48% and 35% of patients, respectively. The most common treatment-emergent AE (TEAE) was all-grade dizziness (63%).

The study remains ongoing to assess long-term outcomes and additional end points.¹

CARE Study

The open-label CARE study enrolled patients with solid tumors harboring ALK, ROS1, and NTRK1-3 alterations with measurable disease and acceptable hematologic, renal, and hepatic function; prior cytotoxic chemotherapy and immunotherapy was allowed.¹

The phase 1 portion included patients under 12 years of age and the phase 2 portion enrolled those aged 12 to25 years old. The trial comprised 3 cohorts based on TRK TKI status and NTRK-positivity.⁵

Repotrectinib dosing varied by age, with weight-based dosing for patients younger than 12 years of age and 160 mg once daily for the first 14 days, followed by potential twice-daily dosing thereafter for patients 12 to25 years of age. Primary outcomes for phase 1 were safety and identifying the recommended phase 2 dose;secondary end points included assessing repotrectinib's antitumor activity and efficacy in pediatric and adult patients under 25 years. The safety analysis included 10 treated patients, and the preliminary efficacy analysis included 8 evaluable patients.

At the August 2, 2021, data cutoff, 10 patients received repotrectinib at 2 dose levels. Complete responses were achieved by 3 of the 4 TKI-naive patients in the efficacy population, one of whom had NTRK-positive glioblastoma multiforme or high-grade glioma. That patient, who previously underwent tumor resection, whole brain radiation, and received multiagent chemotherapy, continued to respond for longer than 3.8 months. The other 2 patients who had a CR continued to respond for longer than 7.3 months and longer than 12.1 months, respectively.

In the TKI-pretreated subset (n = 4), 1 patient with NTRK fusion–positive sarcoma achieved stable disease.

The most common treatment-emergent AEs included anemia (n = 5) and fatigue (n = 5). Three of the 5 patients who experienced anemia had a baseline history of the toxicity, and four patients experienced grade 1/2 dizziness. No patients discontinued repotrectinib for reasons other than disease progression, and no dose reductions or dose-limiting toxicities were observed.