Bristol Myers Squibb announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Augtyro? (repotrectinib) for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. The approval is based on results from the Phase 1/2 TRIDENT-1 study, which evaluated Augtyro in adult patients with NTRK-positive solid tumors.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The TRIDENT-1 trial included both TKI-naïve (n=40) and TKI-pretreated (n=48) patients with NTRK-positive locally advanced/metastatic solid tumors collectively representing 15 different types of cancer.

In TKI-naïve patients, with a median follow up of 17.8 months, 58% (95% CI: 41 to 73) had a confirmed objective response rate (cORR); of those, 43% experienced partial responses (PR) and 15% had complete responses (CR). 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% (95% CI: 35 to 65); of those, 50% experienced PR and no patients achieved CR.

Additionally, 42% of TKI-pretreated responding patients were still in response at one year with Augtyro. The mDOR was 9.9 months (95% CI: 7.4 to 13.0). Among those who had measurable central nervous system (CNS) metastases at baseline, intracranial response was observed in 2 out of 2 TKI-naïve patients and in 3 out of 3 TKI-pretreated patients.

Augtyro is associated with the following Warnings & Precautions: central nervous system (CNS) effects, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity. Please see Important Safety Information below. Based on clinical and pharmacokinetic data, the recommended dose for Augtyro for pediatric patients aged 12 years and older is the same as for adults, 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 have not been established in pediatric patients younger than 12 years of age with solid tumors who have an NTRK gene fusion. This is the second indication for Augtyro in the U.S., following its full approval for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC in November 2023. TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of Augtyro in patients with locally advanced or metastatic neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive (NTRK1/2/3) solid tumors.

The trial excludes patients with symptomatic brain metastases, among other exclusion criteria. Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose.5 Phase 2 of the trial in NTRK-positive locally advanced/metastatic solid tumor cohorts has a primary endpoint of objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR).5 Among others, key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by BICR, and intracranial response in patients with measurable brain metastases. The safety profile for Augtyro was evaluated in 426 patients who received Augtyro in the TRIDENT-1 pivotal trial.1 Permanent discontinuation of Augtyrodue to an adverse reaction occurred in 7% of patients.

There were no specific adverse reactions that accounted for =1% of permanent discontinuations. Augtyro dosage was interrupted due to an adverse reaction in 50% of patients, and dose reductions due to an adverse reaction occurred in 38% of patients.1 Serious adverse reactions occurred in 35% of patients who received Augtyro.1Serious adverse reactions in =2% of patients included pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%) and hypoxia (2.6%). Fatal adverse reactions occurred in 3.5% of patients who received Augtyro, including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.1 The most common (=20%) adverse reactions were dizziness (65%), dysgeusia (54%), peripheral neuropathy (49%), constipation (38%), dyspnea (30%), fatigue (30%), ataxia (28%), cognitive impairment (25%), muscular weakness (20%) and nausea (20%).

Grade 3 dizziness occurred in 2.8% of patients. Neurotrophic tropomyosin receptor kinase (NTRK) are a family of receptors involved in neural development.6 An NTRK gene fusion is an alteration that occurs when a piece of the chromosome containing the NTRK gene breaks off and joins with a gene on another chromosome. These fusions lead to abnormal proteins, which may cause cancer cells to grow.

While NTRK gene fusions are rare in patients with solid tumors, testing for NTRK gene fusions allows for the identification of patients who may benefit from TRK inhibitor therapy. AUGTYRO? is indicated for the treatment of: adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) adult and pediatric patients 12 years of age and older with solid tumors that: have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).