The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended repotrectinib (Augtyro, Bristol Myers Squibb) for approval in the European Union. The recommendation covers the treatment of adult patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) and adult and pediatric patients aged 12 years and older with advanced NTRK fusion-positive solid tumors.
The NTRK fusion-positive indication is specific to patients who have either received a prior NTRK inhibitor or have not received a prior NTRK inhibitor and whose tumors are such that therapies that do not target NTRK provide limited clinical benefit, or have been exhausted.
This recommendation is based on data from the phase 1/2 TRIDENT-1 trial (NCT03093116) and the phase 1/2 CARE trial (NCT04094610). These studies demonstrated durable activity and robust responses in adult and pediatric patients with advanced ROS1-positive NSCLC and advanced NTRK-positive solid tumors, respectively.
Joseph Fiore, global program lead for repotrectinib and vice president of Bristol Myers Squibb, noted the significant unmet need for new therapies in the EU for patients with ROS1-positive NSCLC and NTRK-positive solid tumors, particularly to address treatment resistance. He expressed anticipation for the European Commission’s decision and the potential to bring this next-generation treatment to patients with tumors harboring ROS1 or NTRK fusions in the EU.
TRIDENT-1 Trial Results
Findings from the TRIDENT-1 trial, published in The New England Journal of Medicine, showed promising results in patients with ROS1 fusion-positive NSCLC. Among patients who had not received a prior ROS1 inhibitor (n = 71), the confirmed objective response rate (ORR) was 79% (95% CI, 68%-88%), with 7 complete responses (CRs) and 49 partial responses (PRs). The median time to response was 1.8 months (range, 0.9-5.6), and the median duration of response (DOR) was 34.1 months (95% CI, 25.6-not estimable).
In patients who had previously received a ROS1 TKI (n = 56), the confirmed ORR was 38% (95% CI, 25%-52%), including 3 CRs and 18 PRs. The median time to response was 1.8 months (range, 1.6-3.6), and the median DOR was 14.8 months (95% CI, 7.6-NE).
In the TRIDENT-1 trial, patients received repotrectinib at 160 mg once daily for 14 days, followed by 160 mg twice daily. The primary endpoint for the phase 2 portion was confirmed ORR as assessed by blinded independent central review. Secondary endpoints included DOR, clinical benefit, and safety.
The most common treatment-related adverse event (TRAE) was dizziness (58% any-grade; 3% grade 3 or higher). Treatment discontinuation due to TRAEs occurred in 3% of patients, with 35% experiencing TRAEs leading to dose reduction and 35% to dose interruption.
CARE Study Details
The phase 1/2 CARE study is evaluating the safety, tolerability, pharmacokinetics, and clinical activity of repotrectinib in pediatric and young adult patients with advanced or metastatic solid tumors harboring ALK, ROS1, or NTRK1-3 alterations.
The phase 1 portion's primary endpoints include dose-limiting toxicities and the recommended phase 2 dose. Secondary endpoints include ORR, clinical benefit rate (CBR), time to response (TTR), DOR, and intracranial ORR. The phase 2 portion's primary endpoint is ORR, with secondary endpoints including CBR, TTR, DOR, intracranial ORR, progression-free survival, and overall survival.
Prior FDA Approvals
Repotrectinib received FDA approval in November 2023 for adult patients with locally advanced or metastatic ROS1-positive NSCLC, based on TRIDENT-1 trial data. It also received accelerated approval in June 2024 for patients 12 years and older with locally advanced or metastatic solid tumors harboring an NTRK gene fusion who are unsuitable for surgical resection, based on TRIDENT-1 and CARE trials.
