EU Approval Recommended for Repotrectinib in ROS1+ NSCLC, NTRK+ Solid Tumors

Results from the TRIDENT-1 and CARE trials, which showcased durable activity and robust responses with repotrectinib, supported the recommendation.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use has recommended the approval of repotrectinib (Augtyro) for 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, according to a news release from the drug’s developer, Bristol Myers Squibb.¹

The NTRK fusion–positive indication is also specific to those who have received a prior NTRK inhibitor or have not received a prior NTRK inhibitor and therapies that do not target NTRK provide limited clinical benefit, or have been exhausted.

The recommendation was supported by results from the phase 1/2 TRIDENT-1 trial (NCT03093116) and the phase 1/2 CARE trial (NCT04094610). In each study, repotrectinib elicited durable activity and robust responses in adult or pediatric patients, respectively, with advanced ROS1-positive NSCLC and advanced NTRK-positive solid tumors.

“Patients in the [European Union] with ROS1-positive non–small cell lung cancer and NTRK-positive solid tumors face a great unmet need for new therapies that may improve their outcomes and address or delay the difficult issue of treatment resistance,” Joseph Fiore, global program lead for repotrectinib and vice president of Bristol Myers Squibb, stated in the press release.¹ “We look forward to the [European Commission’s] upcoming decision and to potentially bringing this next-generation treatment to patients with tumors harboring ROS1 or NTRK fusions in the [European Union].”

Repotrectinib received FDA approval in November 2023 for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC, based on data from the phase 1/2 TRIDENT-1 trial.²

Repotrectinib additionally received accelerated approval in June 2024 as a treatment for patients 12 years and older with locally advanced or metastatic solid tumors that are unsuitable for surgical resection and harbor an NTRK gene fusion based on data from the phase 1/2 TRIDENT-1 and CARE trials.³

TRIDENT-1 Trial

Findings published in The New England Journal of Medicine show that among patients with ROS1 fusion–positive NSCLC who had not received a prior ROS1 inhibitor (n = 71), 56 reported a confirmed response (79%; 95% CI, 68%-88%), including 7 complete responses (CRs) and 49 partial responses (PRs).⁴ The median time to response for this patient population 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 [NE]).

Furthermore, of the 56 patients who had previously received a ROS1 TKI, 21 (38%; 95% CI, 25%-52%) had confirmed responses, including 3 CRs and 18 PRs. Additionally, 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 TRIDENT-1, patients received 160 mg of repotrectinib once daily for 14 days followed by 160 mg twice daily. The phase 2 portion’s primary end point was confirmed ORR as assessed by blinded independent central review. Secondary end points included DOR, clinical benefit, and safety.

The most common treatment-related adverse effect (TRAE) was dizziness (58% any-grade; 3% grade 3 or higher). Additionally, 3% of patients discontinued treatment due to TRAEs, 35% had a TRAE leading to dose reduction, and 35% had a TRAE leading to dose interruption.

CARE Study

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.⁵

The phase 1 portion’s primary end points include dose-limiting toxicities and the recommended phase 2 dose. Secondary end points include ORR, clinical benefit rate (CBR), time to response (TTR), DOR, and intracranial ORR. The phase 2 portion primary end point is ORR. Secondary end points will include CBR, TTR, DOR, intracranial ORR, progression-free survival, and overall survival.

References

1. Bristol Myers Squibb receives positive CHMP opinion for repotrectinib for the treatment of advanced ROS1-positive non-small cell lung cancer and advanced NTRK-positive solid tumors. News release. Bristol Myers Squibb. November 15, 2024. Accessed November 19, 2024. https://tinyurl.com/35nr46p9
2. FDA approves repotrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. November 15, 2023. https://tinyurl.com/327fb6eb
3. 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. https://tinyurl.com/3csv92ts
4. Drilon A, Camidge DR, Lin JJ, et al. Repotrectinib in ROS1 fusion–positive non–small-cell lung cancer. N Engl J Med. 2024:390(2):118-131. doi:10.1056/NEJMoa2302299
5. A study of repotrectinib in pediatric and young adult subjects harboring ALK, ROS1, OR NTRK1-3 alterations. ClinicalTrials.gov. Updated November 13, 2024. Accessed November 19, 2024. https://tinyurl.com/bdad9m7h