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EGFR Inhibitor

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EGFR Inhibitor, Epidermal Growth Factor Receptor Inhibitor, Small Molecule EGFR Inhibitor, EGFR Tyrosine Kinase Inhibitor, Afatinib, Gilotrif, Dacomitinib, Vizimpro, Erlotinib, Tarcerva, Gefitinib, Iressa, Osimertinib, Tagrisso, Lapatinib, Tykerb, Neratinib, Nerlynx

  • See Also
  1. EGFR Monoclonal Antibody
  2. Small Molecule Inhibitor-Mediated Chemotherapy
  3. Chemotherapy
  • Indications
  1. Metastatic Lung Non-Small Cell Lung Cancer (EGFR exon 19 deletion, exon 21 substitution)
    1. Afatinib
    2. Dacomitinib
    3. Erlotinib
    4. Gefitinib
    5. Osimertinib
  2. Advanced, metastatic HER2 positive Breast Cancer
    1. Lapatinib
    2. Neratinib
  • Mechanism
  1. Epidermal Growth Factor Receptor (EGFR, HER1)
    1. Tyrosine Kinase that is activated by specific Ligands on cells of epidermal-lineage
    2. Binding triggers cascade that leads to epithelial cell growth, development and homeostasis
    3. May also trigger cancer cell proliferation, invasion and migration
      1. EGFR Tyrosine Kinase mutations and amplifications
      2. Seen in a variety of cancers (e.g. lung, Breast, brain)
  2. EGFR Inhibitors (EGFR Tyrosine Kinase Receptor Inhibitors)
    1. Bind Tyrosine Kinase extracellular region of EGFR (esp. ATP binding site), blocking Ligand binding activation
    2. Many small molecule agents active at EGFR, also block more than one Tyrosine Kinase
    3. Most of the EGFR Inhibitors are quinazoline derivatives (anilino-quinazoline)
  3. Other agents targeting EGFR (HER1)
    1. EGFR Monoclonal Antibody (Cetuximab, Panitumumab, Necitumumab)
  • Medications
  1. Afatinib (Gilotrif)
    1. Afatinib irreversibly binds and inhibits EGFR (HER1), HER2 and HER4, as well some EGFR mutations
    2. Risk of severe Diarrhea, hepatotoxicity, Interstitial Lung Disease, bullous or exfoliative rash, Keratitis
  2. Dacomitinib (Vizimpro)
    1. Dacomitinib irreversibly binds and inhibits EGFR (HER1), HER2 and HER4
    2. Risk of severe Diarrhea, Interstitial Lung Disease, bullous or exfoliative rash
    3. Avoid with Proton Pump Inhibitor and space at least 6 hours before, 10 hours after H2 Blocker
    4. Avoid in combination with narrow Therapeutic IndexCYP2D6 Substrates
  3. Erlotinib (Tarcerva)
    1. Erlotinib primarily binds EGFR Tyrosine Kinase
    2. Risk of hepatotoxicity, Interstitial Lung Disease, Acute Kidney Injury, bullous or exfoliative rash, GI perforation, Corneal perforation
    3. Risk of Microangiopathic Hemolytic Anemia, cardiovascular events (MI, CVA)
    4. Avoid with Proton Pump Inhibitor and space at least 6 hours before, 10 hours after H2 Blocker
    5. Increases Warfarin levels and INR (monitor)
  4. Gefitinib (Iressa)
    1. Gefitinib primarily binds EGFR Tyrosine Kinase
    2. Gefitinib may also inhibit Angiogenesis and trigger Cell Cycle arrest
    3. Risk of Interstitial Lung Disease, Corneal Erosions
  5. Lapatinib (Tykerb)
    1. Reversibly binds and inhibits EGFR, HER2/neu, Erk-1, Erk-2 and AKT kinases
    2. Also decreases cyclin D Protein levels
    3. Risk of hepatotoxicity, Cardiomyopathy, Prolonged QTc, Interstitial Lung Disease, severe Diarrhea, bullous or exfoliative rash
  6. Neratinib (Nerlynx)
    1. Primarily binds irreversibly and inhibits HER-2 receptor, but also binds and inhibits EGFR Tyrosine Kinase
    2. Risk of severe Diarrhea, hepatotoxicity
  7. Osimertinib (Tagrisso)
    1. Risk of Interstitial Lung Disease (3%), Prolonged QTc, Cardiomyopathy (1.4%)
  8. Vandetanib (Caprelsa)
    1. See VEGF Inhibitor
    2. Primarily blocks Vascular Endothelial Growth Factor receptor 2 (VEGFR2), but also blocks EGFR
  • Dosing
  1. See other references for disease specific dosing protocols
  • Safety
  1. Avoid in Lactation (and for 3 weeks after last dose)
  2. Avoid in pregnancy (all trimesters, pregnancy category D or X)
    1. Use reliable Contraception (including for 3 weeks after last dose)
  3. Monitoring
    1. Liver Function Tests
    2. Serum creatitine (Erlotinib)
    3. INR (Erlotinib)
    4. Echocardiogram baseline and every 3 months (Osimertinib, consider for Lapatinib)
  • Efficacy
  1. Osimertinib is highly effective in metastatic EGFR Lung Cancer
  • Adverse Effects
  1. Interstitial Lung Disease (Afatinib, Dacomitinib, Erlotinib, Gefitinib, Osimertinib, Lapatinib)
  2. Acute Kidney Injury (Erlotinib)
  3. Microangiopathic Hemolytic Anemia (Erlotinib)
  4. Cardiovascular
    1. Prolonged QTc (Osimertinib, Lapatinib)
    2. Cardiomyopathy (Osimertinib, Lapatinib)
  5. Gastrointestinal
    1. Severe Diarrhea (Afatinib, Dacomitinib, Lapatinib, Neratinib)
    2. Hepatotoxicity (Afatinib, Erlotinib, Lapatinib, Neratinib)
    3. Gastrointestinal Perforation
  6. Serious Drug Induced bullous or Exfoliative Dermatitis (Afatinib, Dacomitinib, Erlotinib, Lapatinib)
    1. Severe Bullous Disease
    2. Toxic Epidermal Necrolysis
    3. Steven Johnson Syndrome
  7. Eye toxicity
    1. Keratitis (Afatinib)
    2. Trichiasis
    3. Corneal perforation (Erlotinib)
    4. Corneal Erosion (Gefitinib)
  • Drug Interactions
  1. Antacids
    1. Avoid Proton Pump Inhibitor with Dacomitinib, Erlotinib, Neratinib
    2. May space Dacomitinib at least 6 hours before, 10 hours after H2 Blocker
  2. CYP2D6 Substrates with narrow Therapeutic Index
    1. Avoid with Dacomitinib
  3. Moderate to strong CYP3A4 Inhibitor and Inducers
    1. Avoid with Erlotinib, Gefitinib, Osimertinib, Lapatinib, Neratinib
  4. P-gp Substrates with narrow therapeutic range
    1. Avoid with Neratinib, Osimertinib
  5. Warfarin
    1. Increased INR (monitor) with Erlotinib, Lapatinib
  • Resources
  1. Afatinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fd638e5e-8032-e7ca-0179-95e96ab5d387
  2. Dacomitinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4ab27d2f-e385-4e9c-b324-fa69c10b855a
  3. Erlotinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20
  4. Gefitinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=827d60e8-7e07-41b7-c28b-49ef1c4a5a41
  5. Lapatinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eee37f88-ec6a-4c30-b8aa-e2c71f93088c
  6. Neratinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d1e41dcf-e82a-47c2-a0ad-6c6eef621834
  7. Osimertinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7
  8. Vandetanib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a883a3a8-d7a1-8a42-d974-2ba29079b602
  • References
  1. Abourehab (2021) Molecules 26(21):6677 +PMID: 34771085 [PubMed]
  2. Zhang (2023) Pharmacol Rev 75(6):1218-1232 +PMID: 37339882 [PubMed]