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U.S. Food and Drug Administration Approves Augtyro (repotrectinib) for Treating NTRK-Positive Advanced Solid Tumors | iPharmaCenter

BMS has announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to Augtyro (repotrectinib) for treating adults and children aged 12 years and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion.

This approval applies to tumors that are locally advanced or metastatic, where surgical removal would result in severe morbidity, or where the tumors have progressed following treatment or have no satisfactory alternative therapy. The decision is based on results from the Phase 1/2 TRIDENT-1 study, which evaluated Augtyro in patients with NTRK-positive solid tumors. This indication is approved based on overall response rate and duration of response, with continued approval contingent upon verification of clinical benefit in confirmatory trials.

TRIDENT-1 Study Results

The TRIDENT-1 trial included both TKI-naïve (n=40) and TKI-pretreated (n=48) patients with NTRK-positive locally advanced or metastatic solid tumors, representing 15 different types of cancer.

  • In TKI-naïve patients, with a median follow-up of 17.8 months, 58% had a confirmed objective response rate (cORR); of those, 43% experienced partial responses (PR) and 15% had complete responses (CR).

  • Among the TKI-naïve patients who responded, 83% remained in response at one year, and the median duration of response (mDOR) was not yet reached.

  • In TKI-pretreated patients, with a median follow-up of 20.1 months, the cORR was 50%; of those, 50% experienced PR, with no CRs. Additionally, 42% of TKI-pretreated responding patients were still in response at one year, and the mDOR was 9.9 months.

Intracranial response was observed in all patients with measurable CNS metastases at baseline, including both TKI-naïve and TKI-pretreated groups.

Safety Information and Dosage

Augtyro is associated with several warnings and precautions, including central nervous system effects, interstitial lung disease/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity. The recommended dose for Augtyro in both adults and pediatric patients aged 12 years and older is 160 mg orally once daily for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicity. The safety and effectiveness of Augtyro in pediatric patients younger than 12 years of age have not been established.

Background and Trial Details

This is the second indication for Augtyro in the U.S., following its full approval for treating adults with locally advanced or metastatic ROS1-positive NSCLC in November 2023.

The TRIDENT-1 trial is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial assessing the safety, tolerability, pharmacokinetics, and anti-tumor activity of Augtyro in patients with locally advanced or metastatic NTRK gene fusion-positive solid tumors. Phase 1 included dose escalation to determine the recommended Phase 2 dose. Phase 2, focused on NTRK-positive cohorts, primarily aims to measure the objective response rate as assessed by Blinded Independent Central Review (BICR). Key secondary endpoints include duration of response and intracranial response in patients with measurable brain metastases.

Understanding NTRK Gene Fusions

Neurotrophic tropomyosin receptor kinase (NTRK) receptors are crucial for neural development. An NTRK gene fusion occurs when a chromosome segment containing the NTRK gene breaks and joins another chromosome, leading to abnormal proteins that can drive cancer cell growth. While NTRK gene fusions are rare in solid tumors, identifying these fusions through testing allows for targeted treatment with TRK inhibitors, offering potential benefits to affected patients.


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