II. Indications
- Metastatic Lung Non-Small Cell Lung Cancer (EGFR exon 19 deletion, exon 21 substitution)
- Afatinib
- Dacomitinib
- Erlotinib
- Gefitinib
- Osimertinib
- Advanced, metastatic HER2 positive Breast Cancer
- Lapatinib
- Neratinib
III. Mechanism
-
Epidermal Growth Factor Receptor (EGFR, HER1)
- Tyrosine Kinase that is activated by specific Ligands on cells of epidermal-lineage
- Binding triggers cascade that leads to epithelial cell growth, development and homeostasis
- May also trigger cancer cell proliferation, invasion and migration
- EGFR Tyrosine Kinase mutations and amplifications
- Seen in a variety of cancers (e.g. lung, Breast, brain)
- EGFR Inhibitors (EGFR Tyrosine Kinase Receptor Inhibitors)
- Bind Tyrosine Kinase extracellular region of EGFR (esp. ATP binding site), blocking Ligand binding activation
- Many small molecule agents active at EGFR, also block more than one Tyrosine Kinase
- Most of the EGFR Inhibitors are quinazoline derivatives (anilino-quinazoline)
IV. Medications
- Afatinib (Gilotrif)
- Dacomitinib (Vizimpro)
- Dacomitinib irreversibly binds and inhibits EGFR (HER1), HER2 and HER4
- Risk of severe Diarrhea, Interstitial Lung Disease, bullous or exfoliative rash
- Avoid with Proton Pump Inhibitor and space at least 6 hours before, 10 hours after H2 Blocker
- Avoid in combination with narrow Therapeutic IndexCYP2D6 Substrates
- Erlotinib (Tarcerva)
- Erlotinib primarily binds EGFR Tyrosine Kinase
- Risk of hepatotoxicity, Interstitial Lung Disease, Acute Kidney Injury, bullous or exfoliative rash, GI perforation, Corneal perforation
- Risk of Microangiopathic Hemolytic Anemia, cardiovascular events (MI, CVA)
- Avoid with Proton Pump Inhibitor and space at least 6 hours before, 10 hours after H2 Blocker
- Increases Warfarin levels and INR (monitor)
- Gefitinib (Iressa)
- Gefitinib primarily binds EGFR Tyrosine Kinase
- Gefitinib may also inhibit Angiogenesis and trigger cell cycle arrest
- Risk of Interstitial Lung Disease, Corneal Erosions
- Lapatinib (Tykerb)
- Reversibly binds and inhibits EGFR, HER2/neu, Erk-1, Erk-2 and AKT kinases
- Also decreases cyclin D Protein levels
- Risk of hepatotoxicity, Cardiomyopathy, Prolonged QTc, Interstitial Lung Disease, severe Diarrhea, bullous or exfoliative rash
- Neratinib (Nerlynx)
- Primarily binds irreversibly and inhibits HER-2 receptor, but also binds and inhibits EGFR Tyrosine Kinase
- Risk of severe Diarrhea, hepatotoxicity
- Osimertinib (Tagrisso)
- Risk of Interstitial Lung Disease (3%), Prolonged QTc, Cardiomyopathy (1.4%)
-
Vandetanib (Caprelsa)
- See VEGF Inhibitor
- Primarily blocks Vascular Endothelial Growth Factor receptor 2 (VEGFR2), but also blocks EGFR
V. Dosing
- See other references for disease specific dosing protocols
VI. Safety
- Avoid in Lactation (and for 3 weeks after last dose)
- Avoid in pregnancy (all trimesters, pregnancy category D or X)
- Use reliable Contraception (including for 3 weeks after last dose)
- Monitoring
- Liver Function Tests
- Serum creatitine (Erlotinib)
- INR (Erlotinib)
- Echocardiogram baseline and every 3 months (Osimertinib, consider for Lapatinib)
VII. Efficacy
- Osimertinib is highly effective in metastatic EGFR Lung Cancer
VIII. Adverse Effects
- Interstitial Lung Disease (Afatinib, Dacomitinib, Erlotinib, Gefitinib, Osimertinib, Lapatinib)
- Acute Kidney Injury (Erlotinib)
- Microangiopathic Hemolytic Anemia (Erlotinib)
- Cardiovascular
- Prolonged QTc (Osimertinib, Lapatinib)
- Cardiomyopathy (Osimertinib, Lapatinib)
- Gastrointestinal
- Severe Diarrhea (Afatinib, Dacomitinib, Lapatinib, Neratinib)
- Hepatotoxicity (Afatinib, Erlotinib, Lapatinib, Neratinib)
- Gastrointestinal Perforation
- Serious Drug Induced bullous or Exfoliative Dermatitis (Afatinib, Dacomitinib, Erlotinib, Lapatinib)
- Severe Bullous Disease
- Toxic Epidermal Necrolysis
- Steven Johnson Syndrome
- Eye toxicity
- Keratitis (Afatinib)
- Trichiasis
- Corneal perforation (Erlotinib)
- Corneal Erosion (Gefitinib)
IX. Drug Interactions
-
Antacids
- Avoid Proton Pump Inhibitor with Dacomitinib, Erlotinib, Neratinib
- May space Dacomitinib at least 6 hours before, 10 hours after H2 Blocker
-
CYP2D6 Substrates with narrow Therapeutic Index
- Avoid with Dacomitinib
- Moderate to strong CYP3A4 Inhibitor and Inducers
- Avoid with Erlotinib, Gefitinib, Osimertinib, Lapatinib, Neratinib
-
P-gp Substrates with narrow therapeutic range
- Avoid with Neratinib, Osimertinib
-
Warfarin
- Increased INR (monitor) with Erlotinib, Lapatinib
X. Resources
- Afatinib (DailyMed)
- Dacomitinib (DailyMed)
- Erlotinib (DailyMed)
- Gefitinib (DailyMed)
- Lapatinib (DailyMed)
- Neratinib (DailyMed)
- Osimertinib (DailyMed)
- Vandetanib (DailyMed)