II. Indications
- NTKR Fusion Solid Tumors (all cancers with specific NTRK-related genetic mutation)
III. Mechanism
- Neurotrophic Tropomyosin Receptor Kinase (NTRK ot TRK)
- Tropomyosin Receptor Kinase (TRK) is activated by neurotrophic growth factors
- When bound, TRKs are activated, triggering a phosphorylation cascade, ultimately triggering the MAPK pathway
- TRK Inhibitors
- Block NTRK binding by neurotrophic growth factors
IV. Medications
- Larotrectinib (Vitrakvi)
- Entrectinib (Rozlytrek)
- Also a ROS1 Inhibitor
- Risk of Neurotoxicity, Hepatotoxicity, skeletal Fractures, cardiotoxicity, Prolonged QTc, Hyperuricemia, ocular toxicity
- Avoid with strong CYP3A4 Inhibitors and inducers
V. Dosing
- See other references for disease specific dosing protocols
- FDA approved for both adults and children with NTRK Fusion Solid Tumors
VI. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters, pregnancy category X)
- Use reliable Contraception
- Monitoring
- Liver Function Tests (baseline and every 2 weeks)
- Echocardiogram (baseline for Entrectinib)
- Electrocardiogram for Prolonged QT (Entrectinib)
VII. Adverse Effects
- Neurotoxicity (Larotrectinib, Entrectinib)
- Hepatotoxicity with elevated transaminases (Larotrectinib, Entrectinib)
- Skeletal Fractures (Larotrectinib, Entrectinib)
- Cardiotoxicity or Cardiomyopathy (Entrectinib)
- Prolonged QTc (Entrectinib)
- Hyperuricemia (Entrectinib)
- Ocular Toxicity or Vision disorders (Entrectinib)
- Gastrointestinal
VIII. Drug Interactions
- Strong CYP3A4 Inhibitors
- Avoid with Larotrectinib and Entrectinib
- If interaction unavoidable, decrease Larotrectinib or Entrectinib dose
- Strong CYP3A4 Inducers
- Avoid with Larotrectinib and Entrectinib
- If interaction unavoidable, increase Larotrectinib or Entrectinib dose
-
CYP3A4 Substrates with narrow Therapeutic Index
- Avoid with Larotrectinib
-
Medication Causes of QTc Prolongation
- Avoid with Entrectinib
IX. Resources
- Larotrectinib (DailyMed)
- Entrectinib (DailyMed)