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 adult patients with ROS1-positive advanced non-small cell lung cancer (NSCLC), and for adult and pediatric patients (12 years and older) with advanced solid tumors harboring NTRK gene fusions. This recommendation includes patients who have received a prior NTRK inhibitor or those for whom non-NTRK-targeting treatments offer limited clinical benefit or have been exhausted.
The positive opinion stems from data derived from the phase 1/2 TRIDENT-1 (NCT03093116) and CARE (NCT04094610) trials. These trials demonstrated that repotrectinib yielded clinically meaningful overall response rates (ORRs) in patients with ROS1-positive NSCLC and NTRK-positive solid tumors.
The European Commission (EC) is slated to review the CHMP recommendation, with a final decision regarding potential approval anticipated in January 2025.
Clinical Efficacy in ROS1-Positive NSCLC
Data from the TRIDENT-1 trial showed promising results in ROS1-positive NSCLC. In patients who were ROS1 TKI-naive (n = 71), the ORR was 79% (95% CI, 68%-88%), with a median duration of response (DOR) of 34.1 months (95% CI, 25.6-Not Estimable [NE]). The median progression-free survival (PFS) in this group was 35.7 months (95% CI, 27.4-NE).
For patients with ROS1-positive NSCLC previously treated with a ROS1 TKI but 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).
Clinical Efficacy in NTRK-Positive Solid Tumors
In NTRK-positive solid tumors, repotrectinib also demonstrated significant activity. Among patients naive to prior TRK TKIs (n = 40), the confirmed ORR was 58% (95% CI, 41%-73%), including a complete response (CR) rate of 12% and a partial response (PR) rate of 45%. The clinical benefit rate (CBR) was 80% (95% CI, 64%-91%), with a median time to response of 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%), consisting entirely of partial responses. The CBR was 75% (95% CI, 60%-86%), and the median time to response was 1.9 months (range, 1.7-3.7).
TRIDENT-1 Trial Design
The phase 1 portion of the TRIDENT-1 trial included patients with locally advanced or metastatic solid tumors harboring ROS1, NTRK, or ALK gene fusions. Phase 2 comprised four cohorts of patients with ROS1-positive NSCLC and two cohorts of patients with NTRK-positive advanced solid tumors.
The dose of repotrectinib selected for phase 2, based on phase 1 data, was 160 mg daily for 14 days, followed by 160 mg twice daily.
The primary endpoint in phase 1 was determining the maximum tolerated dose and the recommended phase 2 dose (RP2D). In phase 2, the primary endpoint was blinded independent central review–assessed ORR per RECIST 1.1 criteria. Secondary endpoints included DOR, CBR, PFS, overall survival, safety, and patient-reported outcomes. Intracranial response was also assessed in patients with measurable brain metastases at baseline.
Among patients treated at the RP2D (n = 426), common treatment-related adverse effects (TRAEs) included dizziness (58%), dysgeusia (50%), and paresthesia (30%). TRAEs led to treatment discontinuation in 3% of patients.
CARE Trial Data
The CARE trial evaluated repotrectinib in pediatric and young adult patients. Early findings reported in 2021 showed confirmed responses in 3 of 8 evaluable patients naive to a prior TKI, including two with NTRK-positive solid tumors and one with a ROS1-positive inflammatory myofibroblastic tumor. In four patients with TKI-pretreated solid tumors, one patient had a best response of stable disease.
In the CARE trial, patients less than 12 years of age received repotrectinib in a capsule or suspension formulation using weight-based dosing, while those between 12 and 25 years of age received repotrectinib at 160 mg once per day for the first 14 days, with the option to increase to 160 mg twice per day thereafter.
No dose-limiting toxicities (DLTs) were reported in evaluable patients (n = 10). The most common treatment-emergent adverse events included anemia (n = 5) and fatigue (n = 5).
