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China’s NMPA has accepted an sNDA for review, seeking the approval of repotrectinib for advanced solid tumors harboring NTRK fusions.
Repotrectinib for NTRK+ Solid Tumors
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China’s National Medical Products Administration has accepted a supplemental new drug application (sNDA) seeking the approval of repotrectinib (Augtyro) for the treatment of adult patients with locally advanced or metastatic solid tumors harboring NTRK gene fusions who have either progressed following prior therapies or have no satisfactory alternative treatment options.1
Repotrectinib was evaluated in patients with NTRK gene fusion–positive advanced solid tumors in the phase 1/2 TRIDENT-1 study (NCT03093116). Data from the study presented at the 2023 ESMO Congress demonstrated that at a median follow-up of 17.8 months, the TKI delivered a confirmed objective response rate (ORR) of 58% (95% CI, 41%-73%) in patients naive to a TRK TKI (n = 40).2 At a median follow-up of 20.1 months for patients previously treated with a TRK TKI (n = 48), the confirmed ORR was 50% (95% CI, 35%-65%).
“NTRK fusion–positive tumors represent a significant therapeutic challenge, particularly in the setting of acquired resistance to existing TRK TKIs,” Rafael Amado, MD, president, and head of Global Research and Development at Zai Lab, stated in a news release.1 “There are no approved treatments for NTRK-positive cancers for both TKI-naive and TKI-pretreated patients in China. Repotrectinib has the potential to become a next-generation TKI that can be used across a broad range of NTRK fusion–positive solid tumors in both settings.”
In May 2024, the FDA granted accelerated approval to repotrectinib for adult and pediatric patients aged 12 years 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 This decision was supported by findings from TRIDENT-1.
The phase 1/2 study enrolled patients with locally advanced or metastatic solid tumors harboring NTRK gene fusions or ROS1 fusions.2 Phase 2 included dose-expansion cohorts for those with NTRK-positive locally advanced or metastatic solid tumors. Patients with asymptomatic central nervous system metastases were permitted to enroll.
During phase 1, the recommended phase 2 dose (RP2D) of repotrectinib was established at 160 mg per day for 14 days, then 160 mg twice per day thereafter. Patients with an NTRK gene fusion–positive solid tumor treated during phase 2 were assigned to cohorts based on prior TKI exposure.
The primary end point of phase 2 was confirmed ORR per blinded independent central review. Secondary end points included duration of response (DOR), clinical benefit rate (CBR), time to response (TTR), ORR in patients previously treated with a TKI, progression-free survival (PFS), overall survival (OS), intracranial ORR, and safety.
Further data from the TKI-naive cohort demonstrated that the median DOR was not evaluable (NE), and the median PFS was NE (95% CI, 5.5-NE). In the TKI-pretreated cohort, the median DOR and median PFS was 9.8 months (95% CI, 7.4-12.9) and 7.4 months (95% CI, 3.9-9.7), respectively.
In patients with NTRK-positive non–small cell lung cancer (NSCLC) treated in the TKI-naive cohort (n = 21), the confirmed ORR was 62% (95% CI, 38%-82%), the CBR was 86% (95% CI, 64%-97%), the 12-month DOR rate was 92% (95% CI, 76%-100%), the 12-month PFS rate was 64% (95% CI, 43%-86%), and the median TTR was 1.8 months (range, 1.6-3.9). Among TKI-exposed patients with NTRK-positive NSCLC (n = 14), the confirmed ORR was 43% (95% CI, 18%-71%), the CBR was 57% (95% CI, 29%-82%), the 12-month DOR rate was 44% (95% CI, 1%-88%), the 12-month PFS rate was 23% (95% CI, 0%-49%), and the median TTR was 1.9 months (range, 1.8-2.0)
Regarding safety, patients with NTRK-positive solid tumors treated with the RP2D of repotrectinib (n = 104) experienced any-grade treatment-emergent adverse effects (TEAEs) at a rate of 98% and any-grade treatment-related AEs (TRAEs) at a rate of 97%. Grade 3 or higher TEAEs and grade 3 or higher TRAEs were reported in 57% and 35% of patients, respectively. The respective rates of serious TEAEs were 39% and 14%. TEAEs led to death in 6% of patients, and no TRAEs led to death
TEAEs led to dose reductions, dose interruptions, and treatment discontinuation in 48%, 52%, and 8% of patients, respectively. The respective rates of TRAEs leading to dose reductions, dose interruptions, and treatment discontinuation were 46%, 40%, and 3%.
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