Repotrectinib Garners Positive CHMP Opinion for ROS1+ NSCLC and NTRK+ Solid Tumors

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending the approval of repotrectinib (Augtyro) for the treatment for adult patients with ROS1-positive advanced non–small cell lung cancer (NSCLC); and for adult and pediatric patients 12 years of age and older with advanced solid tumors harboring NTRK gene fusions who have received a prior NTRK inhibitor or have not received a prior NTRK inhibitor and treatment options not targeting NTRK provide limited clinical benefit or have been exhausted.¹

The positive opinion was based on data from the phase 1/2 TRIDENT-1 (NCT03093116) and CARE (NCT04094610) trials, which showed that patients with ROS1-positive NSCLC and NTRK-positive solid tumors experienced clinically meaningful overall response rates (ORRs) when treated with repotrectinib.

The European Commission (EC) will review the CHMP recommendation, and a final decision regarding potential approval is expected in January 2025.

“Patients in the European Union [EU] with ROS1-positive NSCLC 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, vice president, global program lead for repotrectinib, Bristol Myers Squibb, stated in a news release. “We look forward to the EC’s upcoming decision and to potentially bringing this next-generation treatment to patients with tumors harboring ROS1 or NTRK fusions in the EU.”

In November 2023, the FDA approved repotrectinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC.² Then in June 2024, the regulatory agency approved the agent for adult and pediatric patients 12 years of age and older with solid tumors harboring an NTRK gene fusion that are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed after treatment or have no satisfactory alternative therapy.³ Both approvals were supported by findings from TRIDENT-1.

TRIDENT-1 Data and Overview

Findings from TRIDENT-1 showed that patients with ROS1-positive NSCLC that were naive to a ROS1 TKI (n = 71) experienced an ORR of 79% (95% CI, 68%-88%) and a median duration of response (DOR) of 34.1 months (95% CI, 25.6-not estimable [NE]).⁴ The median progression-free survival (PFS) in this population was 35.7 months (95% CI, 27.4-NE).

In patients with ROS1-positive NSCLC that was previously exposed to a ROS1 TKI and naive to chemotherapy (n = 56), the ORR was 38% (95% CI, 25%-52%), and the median DOR was 14.8 months (95% CI, 7.6-NE). The median PFS was 9.0 months (95% CI, 6.8-19.6).

Patients with NTRK-positive solid tumors naive to a prior TRK TKI (n = 40) achieved a confirmed ORR of 58% (95% CI, 41%-73%), including a complete response (CR) rate of 12% and a partial response (PR) rate of 45%.⁵ The clinical benefit rate (CBR) was 80% (95% CI, 64%-91%), and the median time to response was 1.8 months (range, 1.6-11.0).

In patients with NTRK-positive solid tumors previously treated with a TRK inhibitor (n = 48), the confirmed ORR was 50% (95% CI, 35%-65%), comprised of a 0% CR rate and a 50% PR rate. The CBR was 75% (95% CI, 60%-86%), and the median time to response 1.9 (range, 1.7-3.7).

The phase 1 portion of the trial included patients with locally advanced or metastatic solid tumors harboring ROS1, NTRK, or ALK gene fusions.⁴ Phase 2 included 4 cohorts of patients with ROS1-positive NSCLC and 2 cohorts of patients with NTRK-positive advanced solid tumors.

Based on phase 1 data, 160 mg of repotrectinib daily for 14 days, followed by 160 mg twice daily was selected as the dose for phase 2.

The primary end point in phase 1 was determining the maximum tolerated dose and the recommended phase 2 dose (RP2D). The primary end point in phase 2 was blinded independent central review–assessed ORR per RECIST 1.1 criteria. Secondary end points for phase 2 were comprised of DOR, CBR, PFS, overall survival, safety, and patient-reported outcomes. Intracranial response per modified RECIST 1.1 criteria was also assessed in patients with measurable brain metastases at baseline.

Among patients treated at the RP2D (n = 426), the most common any-grade treatment-related adverse effects (TRAEs) included dizziness (58%), dysgeusia (50%), and paresthesia (30%). TRAEs led to treatment discontinuation in 3% of patients.

CARE Data and Overview

Findings from CARE reported in 2021 showed that among pediatric and young adult patients with advanced solid tumors harboring ALK, ROS1 or NTRK alterations evaluable for efficacy (n = 8), confirmed responses were observed in 3 patients naive to a prior TKI, including 2 with NTRK-positive solid tumors and 1 with a ROS1-positive inflammatory myofibroblastic tumor.⁶ In 4 patients with TKI-pretreated solid tumors, 1 patient had a best response of stable disease.

CARE was designed to evaluate repotrectinib in pediatric and young adult patients; phase 1 included patients less than 12 years of age, and phase 2 featured patients between 12 and 25 years of age.⁷

For patients less than 12 years of age, repotrectinib was administered in a capsule or suspension formulation using weight-based dosing.⁶ Those between 12 and 25 years of age received repotrectinib at 160 mg once per day for the first 14 days and were allowed to increase to 160 mg twice per day on subsequent days.

The incidence of dose-limiting toxicities (DLTs) and determining the RP2D were the primary end points in phase 1; ORR was the primary end point in phase 2.⁷

Regarding safety, no DLTs were reported in evaluable patients (n = 10).⁶ The most common treatment-emergent AEs included anemia (n = 5) and fatigue (n = 5). Notably, 3 of the patients who experienced anemia had a history of anemia at baseline. Dizziness AEs occurred in 4 patients; all events were grade 1 or 2 and did not lead to treatment discontinuation.

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 15, 2024. https://news.bms.com/news/corporate-financial/2024/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/default.aspx
2. FDA approves repotrectinib for ROS1-positive non-small cell lung cancer. FDA. Updated November 16, 2023. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-repotrectinib-ros1-positive-non-small-cell-lung-cancer
3. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-repotrectinib-adult-and-pediatric-patients-ntrk-gene-fusion-positive
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. Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: update from the phase I/II TRIDENT-1 trial. Ann Oncol. 2023;34(suppl 2):S787-S788. doi:10.1016/j.annonc.2023.09.2405
6. Turning Point Therapeutics presents early clinical data for repotrectinib from care study in pediatric and young adult patients at SIOP 2021 Virtual Congress. News release. Turning Point Therapeutics, Inc. October 23, 2021. Accessed November 15, 2024. https://www.globenewswire.com/news-release/2021/10/23/2319431/0/en/Turning-Point-Therapeutics-Presents-Early-Clinical-Data-for-Repotrectinib-From-Care-Study-in-Pediatric-and-Young-Adult-Patients-at-SIOP-2021-Virtual-Congress.html
7. 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 15, 2024. https://clinicaltrials.gov/study/NCT04094610