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NTRK Inhibitor

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NTRK Inhibitor, Neurotrophic Tyrosine Kinase Receptor Antagonist, TRK Inhibitor, Tropomyosin Kinase Receptor Antagonist, Larotrectinib, Vitrakvi, Entrectinib, Rozlytrek

  • See Also
  1. Small Molecule Inhibitor-Mediated Chemotherapy
  2. Chemotherapy
  • Indications
  1. NTKR Fusion Solid Tumors (all cancers with specific NTRK-related genetic mutation)
  • Mechanism
  1. Neurotrophic Tropomyosin Receptor Kinase (NTRK ot TRK)
    1. Tropomyosin Receptor Kinase (TRK) is activated by neurotrophic growth factors
    2. When bound, TRKs are activated, triggering a phosphorylation cascade, ultimately triggering the MAPK pathway
  2. TRK Inhibitors
    1. Block NTRK binding by neurotrophic growth factors
  • Medications
  1. Larotrectinib (Vitrakvi)
    1. Risk of Neurotoxicity, Hepatotoxicity and skeletal Fractures
    2. Avoid with strong CYP3A4 Inhibitors and inducers
  2. Entrectinib (Rozlytrek)
    1. Also a ROS1 Inhibitor
    2. Risk of Neurotoxicity, Hepatotoxicity, skeletal Fractures, cardiotoxicity, Prolonged QTc, Hyperuricemia, ocular toxicity
    3. Avoid with strong CYP3A4 Inhibitors and inducers
  • Dosing
  1. See other references for disease specific dosing protocols
  2. FDA approved for both adults and children with NTRK Fusion Solid Tumors
  • Safety
  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception
  3. Monitoring
    1. Liver Function Tests (baseline and every 2 weeks)
    2. Echocardiogram (baseline for Entrectinib)
    3. Electrocardiogram for Prolonged QT (Entrectinib)
  • Adverse Effects
  1. Neurotoxicity (Larotrectinib, Entrectinib)
    1. Cognitive Impairment
    2. Dizziness
    3. Mood Disorders
  2. Hepatotoxicity with elevated transaminases (Larotrectinib, Entrectinib)
  3. Skeletal Fractures (Larotrectinib, Entrectinib)
  4. Cardiotoxicity or Cardiomyopathy (Entrectinib)
  5. Prolonged QTc (Entrectinib)
  6. Hyperuricemia (Entrectinib)
  7. Ocular Toxicity or Vision disorders (Entrectinib)
  8. Gastrointestinal
    1. Nausea, Diarrhea, Constipation
  • Drug Interactions
  1. Strong CYP3A4 Inhibitors
    1. Avoid with Larotrectinib and Entrectinib
    2. If interaction unavoidable, decrease Larotrectinib or Entrectinib dose
  2. Strong CYP3A4 Inducers
    1. Avoid with Larotrectinib and Entrectinib
    2. If interaction unavoidable, increase Larotrectinib or Entrectinib dose
  3. CYP3A4 Substrates with narrow Therapeutic Index
    1. Avoid with Larotrectinib
  4. Medication Causes of QTc Prolongation
    1. Avoid with Entrectinib
  • Resources
  1. Larotrectinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c8ca614-58b2-4aa4-83d3-0387a8f782fd
  2. Entrectinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c7c71b0c-2549-4495-86b6-c2807fa54908
  • References
  1. Cocco (2018) Nat Rev Clin Oncol 15(12):731-47 +PMID: 30333516 [PubMed]