Monday, July 15, 2024

Solid Tumors with NTRK Gene Fusions Gain Expanded FDA Approval for Repotrectinib Treatment

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Solid tumors with an NTRK gene fusion, whether locally advanced, unresectable, or metastatic, have received accelerated approval for treatment with repotrectinib (Augtyro, Bristol Myers Squibb) from the U.S. Food and Drug Administration (FDA). This approval is specifically for solid tumors that have progressed after initial treatment or for which there are no satisfactory alternative therapies.

This expanded label approval builds on repotrectinib’s initial clearance in November 2023, which was for the treatment of locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). The expansion allows the use of this tyrosine kinase inhibitor (TKI) across a broader range of cancer types.

NTRK gene fusions are genetic abnormalities where a segment of the NTRK gene fuses with another unrelated gene, resulting in the production of an oncogenic protein. Although these mutations are relatively rare, they can occur in various types of cancer. The FDA’s decision to expand the label for repotrectinib underscores the importance of addressing these mutations, given their potential to drive cancer progression.

FDA Approves Repotrectinib for NTRK Gene Fusion Solid Tumors Based on Trial Results

The FDA’s decision was based on results from the TRIDENT-1 trial, a single-arm, open-label study involving 88 adult patients with locally advanced or metastatic NTRK gene fusion-positive solid tumors. The study included both TKI-naive patients and those who had previously been treated with a TKI.

In TKI-naive patients, which comprised 40 participants, the overall response rate was 58%, with a median duration of response that was not estimable at the time of analysis. Among the 48 patients who had received prior TKI treatment, the overall response rate was 50%, with a median duration of response of 9.9 months. These promising results demonstrated repotrectinib’s efficacy in both previously treated and untreated patients.

Treatment with repotrectinib was associated with several side effects occurring in 20% or more of participants. These included dizziness, dysgeusia (distorted taste), peripheral neuropathy, constipation, dyspnea (difficulty breathing), fatigue, ataxia (lack of muscle control), cognitive impairment, muscular weakness, and nausea. Given these adverse effects, the labeling for repotrectinib includes warnings about potential central nervous system reactions, interstitial lung disease/pneumonitis, hepatotoxicity (liver damage), myalgia (muscle pain) with elevated creatine phosphokinase levels, hyperuricemia (elevated uric acid), bone fractures, and embryo-fetal toxicity.

Solid Tumors

FDA Expands Approval of Repotrectinib for NTRK Gene Fusion Solid Tumors

The recommended dosage for repotrectinib is 160 mg taken orally once daily for the first 14 days. After this initial period, the dose is increased to 160 mg taken twice daily, and continued until disease progression or unacceptable toxicity is observed. This dosage regimen aims to balance efficacy with the management of potential side effects.

The expanded approval of repotrectinib represents a significant advancement in the treatment of solid tumors with NTRK gene fusions. It provides a new therapeutic option for patients who have limited or no satisfactory alternatives, addressing a critical unmet need in oncology. The inclusion of both adult and pediatric patients aged 12 years and older broadens the potential impact of this therapy across different age groups.

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Repotrectinib’s expanded label approval by the FDA highlights its potential as a versatile treatment for various solid tumors characterized by NTRK gene fusions. With promising response rates in both TKI-naive and previously treated patients, this therapy offers hope for improved outcomes in cancers that are notoriously difficult to treat with conventional therapies. Despite the associated side effects, the careful management and monitoring of these risks can help maximize the therapeutic benefits of repotrectinib for eligible patients. The ongoing commitment to addressing rare genetic mutations in cancer underscores the evolving landscape of precision medicine and its role in enhancing patient care.

 

Resource: Food and Drug Administration, June 13, 2024

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