General Information
- Drug class: Selective TRK inhibitor
- Approval: FDA-approved in 2018 as one of the first “tumor-agnostic” therapies (approved based on biomarker, not tumor site).
Mechanism of Action
- Inhibits TRK fusion proteins caused by NTRK1, NTRK2, or NTRK3 gene fusions.
- Blocking TRK signaling halts proliferation and survival of fusion-positive tumor cells.
Indications
- Treatment of adult and pediatric patients (≥1 month old) with:
- Solid tumors harboring NTRK gene fusions,
- That are metastatic or surgical resection would cause severe morbidity,
- With no satisfactory alternative treatment or progression after prior therapy.
Dosing
- Adults & children ≥1 month (based on BSA for pediatrics):
- 100 mg orally twice daily (capsules or oral solution).
- Pediatrics (based on BSA):
- 100 mg/m² PO BID (max 100 mg BID).
Administration
- With or without food.
- Oral solution must be used within 90 days of opening.
Adverse Effects
Common:
- Fatigue
- Dizziness, headache
- Nausea, vomiting, constipation, diarrhea
- Increased liver enzymes (ALT, AST)
- Anemia, neutropenia
Serious:
- Neurotoxicity (ataxia, dizziness, cognitive changes)
- Hepatotoxicity
- Weight gain and growth/developmental effects (in pediatrics with long-term use)
Drug Interactions
- CYP3A4 substrate → avoid strong CYP3A4 inducers/inhibitors.
- May require dose adjustments if given with CYP3A modulators.
Monitoring
- Liver function tests (AST/ALT, bilirubin): baseline & monthly
- CBC: periodically
- Neurologic status: monitor for dizziness, gait disturbances
- Growth and development: especially in children
Clinical Pearls
- Tumor-agnostic therapy → approved for any solid tumor type if NTRK fusion is present.
- Generally well tolerated compared to chemotherapy.
- Resistance can develop (via acquired NTRK mutations) → next-gen TRK inhibitors like selitrectinib or repotrectinib may be considered.