Approval Details

On June 13, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval to repotrectinib, marketed as Augtyro by Bristol-Myers Squibb Company, for adult and pediatric patients aged 12 and older with solid tumors that exhibit neurotrophic tyrosine receptor kinase (NTRK) gene fusion. This approval targets patients whose tumors are locally advanced or metastatic, or where surgical resection could lead to severe morbidity. It specifically applies to cases where the disease has progressed following previous treatments or where no satisfactory alternative therapy is available.

Full prescribing information for Augtyro will be made available on the Drugs@FDA website.

Efficacy and Safety

Efficacy of repotrectinib was evaluated in the TRIDENT-1 trial (NCT03093116), a multicenter, single-arm, open-label, multi-cohort study involving 88 adult patients with locally advanced or metastatic NTRK gene fusion-positive solid tumors. The study included both patients who had received a prior TRK tyrosine kinase inhibitor (TKI) (n=48) and those who were TKI-na?ve (n=40). Patients with symptomatic brain metastases were excluded, though all participants were assessed for central nervous system (CNS) lesions at baseline. Tumor assessments were conducted every eight weeks.

The primary measures of efficacy were overall response rate (ORR) and duration of response (DOR) as evaluated by blinded independent central review according to RECIST v1.1 criteria. In the TKI-na?ve group, the confirmed ORR was 58% (95% CI: 41, 73), while the TKI-pretreated group had an ORR of 50% (95% CI: 35, 65). The median DOR was not estimable (NE) (95% CI: NE, NE) in the TKI-na?ve group and was 9.9 months (95% CI: 7.4, 13.0) in the TKI-pretreated group.

Adverse Reactions and Dosage

The most common adverse reactions reported in more than 20% of patients included dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

The recommended dose of repotrectinib is 160 mg orally once daily for the first 14 days, followed by an increase to 160 mg twice daily with or without food, continuing until disease progression or the occurrence of unacceptable toxicity.

Highlights

• The FDA granted accelerated approval to repotrectinib (Augtyro) for patients with NTRK gene fusion-positive solid tumors.
• The approval is for both adult and pediatric patients aged 12 and older.
• The TRIDENT-1 trial demonstrated significant efficacy with a 58% ORR in TKI-na?ve patients and a 50% ORR in TKI-pretreated patients.
• The most common adverse reactions included dizziness, dysgeusia, and peripheral neuropathy among others.
• Recommended dosage involves an initial 160 mg once daily regimen, increasing to twice daily after 14 days.

This development marks a significant advancement in the treatment options available for patients with NTRK gene fusion-positive solid tumors, offering hope for improved outcomes in this patient population.