A Third NTRK-Targeted Treatment Receives FDA Approval: Repotrectinib

Another important step has been taken in cancer treatment. On June 13, 2024, the US Food and Drug Administration (FDA) granted accelerated approval to repotrectinib (AUGTYRO, Bristol-Myers Squibb Company). The approval applies to adult and pediatric patients aged 12 years or older with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive solid tumors that are locally advanced or metastatic and whose surgical resection is likely to cause serious morbidity. These patients have previously received treatment or have no satisfactory alternative treatment option.

This extends the previous indication—locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC)—covered by repotrectinib's FDA approval in November 2023 . Repotrectinib is the first drug specifically approved for ROS1 -positive NSCLC.

NTRK-Targeted Treatments

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are abnormal genetic alterations formed when an NTRK gene joins another gene. There are three main NTRK genes, known as NTRK1, NTRK2 and NTRK3. By transmitting nerve growth factor signals into cells, these genes are essential to nervous system development and function.

NTRK fusions activate signaling pathways that are normally controlled in healthy cells. This uncontrolled activation promotes cell growth and proliferation, which can lead to cancer.

Why NTRK Fusions Matter

NTRK fusions are rare but clinically significant genetic alterations found in various cancer types. They may cause cancer cells to grow and spread continuously. Treatments targeting NTRK fusions offer new, effective options for patients with this genetic abnormality.

NTRK Fusions in Solid Cancers

NTRK fusions occur in various solid tumors arising in tissues and organs. Their frequency is generally low, but they can be more common in some cancer types. For example:

• Infantile fibrosarcoma: Above 90%
• Congenital fibrosarcoma: Above 90%
• Secretory breast carcinoma: Above 90%
• Secretory salivary gland carcinoma: Above 90%

In other solid tumors, NTRK fusion rates are generally below 1% . However, the specific histological type and origin of the tumor can affect these rates. Detecting NTRK fusions is therefore considered an important diagnostic and treatment option in certain cancers.

NTRK Positivity Rates in Other Cancers

• Lung cancer: 0.1-3%
• Colorectal cancer: 0.2-1%
• Thyroid cancer: 2-3% (particularly papillary thyroid carcinoma)
• Pancreatic cancer: Below 1%
• Breast cancer (nonsecretory): 0.1-0.5%
• Gastrointestinal stromal tumor (GIST): 0.1-0.5%
• Biliary tract cancer: 0.5-1%
• Gliomas (brain tumors): 0.5-3%
• Melanoma: Below 0.5%
• Stomach cancer: Below 1%

NTRK fusions in tumor tissue can be detected using the following methods: immunohistochemistry and FISH may be suitable for initial screening, but advanced molecular techniques such as NGS or RNA sequencing are recommended for greater sensitivity and more detailed information.

Repotrectinib is the third NTRK-targeted treatment to receive FDA approval.

The primary endpoints and survival data from the clinical trials supporting FDA approval of NTRK-targeted drugs are listed below:

The New FDA Approval Based on TRIDENT-1

Repotrectinib's efficacy was evaluated in TRIDENT-1 (NCT03093116), a multicenter, single-arm, open-label, multicohort clinical trial.

The trial enrolled 88 adult patients with locally advanced or metastatic NTRK gene fusion-positive solid tumors.

Of these patients, 48 had previously received a TRK tyrosine kinase inhibitor (TKI), while 40 were TKI-naive (had not previously received a TKI).

All patients were assessed for central nervous system (CNS) lesions at baseline, and those with symptomatic brain metastases were excluded. Tumors were assessed every 8 weeks.

Key Efficacy Results

• TKI-Naive Group: Confirmed overall response rate (ORR): 58% (95% CI: 41, 73)
• Previously TKI-Treated Group: ORR: 50% (95% CI: 35, 65)

Median duration of response (DOR) was not estimable (NE) in the TKI-naive group (95% CI: NE, NE) and was 9.9 months (95% CI: 7.4, 13.0) in the previously TKI-treated group.

Most Common Adverse Events

• Dizziness
• Taste disturbance
• Peripheral neuropathy
• Constipation
• Shortness of breath
• Fatigue
• Ataxia
• Cognitive impairment
• Muscle weakness
• Nausea

Dosing

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