II. 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

III. 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)

IV. 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

V. Dosing

  1. See other references for disease specific dosing protocols

VI. 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)

VII. Efficacy

  1. Osimertinib is highly effective in metastatic EGFR Lung Cancer

VIII. 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)

IX. 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

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Related Studies

Ontology: gefitinib (C1122962)

Definition (NCI_NCI-GLOSS) A drug that is used to treat certain types of non-small cell lung cancer and is being studied in the treatment of other types of cancer. It is a type of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.
Definition (NCI) An anilinoquinazoline with antineoplastic activity. Gefitinib inhibits the catalytic activity of numerous tyrosine kinases including the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase-dependent tumor growth. Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction. Gefitinib may also induce cell cycle arrest and inhibit angiogenesis. (NCI04)
Definition (PDQ) An anilinoquinazoline with antineoplastic activity. Gefitinib inhibits the catalytic activity of numerous tyrosine kinases including the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase-dependent tumor growth. Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction. Gefitinib may also induce cell cycle arrest and inhibit angiogenesis. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=43649&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=43649&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1855" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C419708
SnomedCT 398685009, 407100002
English 4-(3Chloro-4-flurophenylamine)-7-methoxy-6(3-(4morpholinyl)quinazoline, 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin] propoxy], gefitinib (medication), gefitinib [Chemical/Ingredient], GEFITINIB, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamide, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) propoxy]-4-quinazolinamine, 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, gefitinib, Gefitinib (product), Gefitinib, Gefitinib (substance)
Spanish gefitinib (producto), gefitinib, gefitinib (sustancia)

Ontology: erlotinib (C1135135)

Definition (NCI) A quinazoline derivative with antineoplastic properties. Competing with adenosine triphosphate, erlotinib reversibly binds to the intracellular catalytic domain of epidermal growth factor receptor (EGFR) tyrosine kinase, thereby reversibly inhibiting EGFR phosphorylation and blocking the signal transduction events and tumorigenic effects associated with EGFR activation.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C400278
SnomedCT 414122006, 414123001
English erlotinib (medication), erlotinib [Chemical/Ingredient], N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine, ERLOTINIB, erlotinib, Erlotinib, Erlotinib (product), Erlotinib (substance)
Spanish erlotinib (producto), erlotinib (sustancia), erlotinib

Ontology: Epidermal growth factor receptor inhibitor (C1443775)

Definition (NCI) Any tyrosine kinase inhibitor that targets the activity of the epidermal growth factor receptor (EGFR) tyrosine kinase. Inhibition of epidermal growth factor receptor tyrosine kinase may inhibit the growth of epidermal-lineage tumor cells, especially those that overexpress epidermal growth factor receptor.
Concepts Pharmacologic Substance (T121)
SnomedCT 409402009, 409403004
English Epidermal Growth-Factor Receptor Inhibitors, EGFR inhibitor, Epidermal growth factor receptor inhibitor (product), Epidermal growth factor receptor inhibitor (substance), Epidermal growth factor receptor inhibitor, EGFR Blocker, EGFR Tyrosine Kinase Inhibitors, EGFR Tyrosine Kinase Inhibitor, EGFR-TK Inhibitor, Epidermal Growth Factor Receptor Inhibitor, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, EGFR Inhibitor
Spanish inhibidor del receptor del factor de crecimiento epidérmico (producto), inhibidor del receptor del factor de crecimiento epidérmico (sustancia), inhibidor del receptor del factor de crecimiento epidérmico

Ontology: lapatinib (C1506770)

Definition (NCI_NCI-GLOSS) A drug used with another anticancer drug to treat breast cancer that is HER2 positive and has advanced or metastasized (spread to other parts of the body) after treatment with other drugs. Lapatinib is also being studied in the treatment of other types of cancer. It is a type of ErbB-2 and EGFR dual tyrosine kinase inhibitor.
Definition (NCI) A synthetic, orally-active quinazoline with potential antineoplastic properties. Lapatinib reversibly blocks phosphorylation of the epidermal growth factor receptor (EGFR), ErbB2, and the Erk-1 and-2 and AKT kinases; it also inhibits cyclin D protein levels in human tumor cell lines and xenografts. EGFR and ErbB2 have been implicated in the growth of various tumor types.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C490728
SnomedCT 425820005, 425466009
English Lapatinib (substance), Lapatinib, Lapatinib (product), lapatinib (medication), lapatinib [Chemical/Ingredient], N-(3-chloro-4-(((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-methylsulfonyl)ethyl)amino)methyl) -2-furyl)-4-quinazolinamine, LAPATINIB, lapatinib
Spanish lapatinib, lapatinib (producto), lapatinib (sustancia)

Ontology: neratinib (C2713008)

Definition (NCI) An orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C487932
English Neratinib, neratinib, NERATINIB
Japanese ネラチニブ

Ontology: dacomitinib (C2987430)

Definition (NCI_NCI-GLOSS) A substance that is being studied in the treatment of cancer. It belongs to the family of drugs called protein tyrosine kinase inhibitors.
Definition (NCI) A highly selective, orally bioavailable small-molecule inhibitor of the HER family of tyrosine kinases with potential antineoplastic activity. Dacomitinib specifically and irreversibly binds to and inhibits human Her-1, Her-2, and Her-4, resulting in the proliferation inhibition and apoptosis of tumor cells that overexpress these receptors.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C525726
English Dacomitinib, (2E)-N-(4-((3-Chloro-4-Fluorophenyl)Amino)-7-Methoxyquinazolin-6-yl)-4-Piperidin-1-ylbut-2-Enamide, dacomitinib, DACOMITINIB

Ontology: Afatinib (C2987648)

Definition (NCI) An orally bioavailable anilino-quinazoline derivative and inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity. Upon administration, afatinib selectively and irreversibly binds to and inhibits the epidermal growth factor receptors 1 (ErbB1; EGFR), 2 (ErbB2; HER2), and 4 (ErbB4; HER4), and certain EGFR mutants, including those caused by EGFR exon 19 deletion mutations or exon 21 (L858R) mutations. This may result in the inhibition of tumor growth and angiogenesis in tumor cells overexpressing these RTKs. Additionally, afatinib inhibits the EGFR T790M gatekeeper mutation which is resistant to treatment with first-generation EGFR inhibitors. EGFR, HER2 and HER4 are RTKs that belong to the EGFR superfamily; they play major roles in both tumor cell proliferation and tumor vascularization and are overexpressed in many cancer cell types.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C522924
SnomedCT 703579002, 703580004
English (2e)-N-(4-(3-Chloro-4-Fluoroanilino)-7-(((3s)-Oxolan-3-yl)Oxy)Quinoxazolin-6-yl)-4-(Dimethylamino)But-2-Enamide, Afatinib, afatinib, AFATINIB, Afatinib (substance), Afatinib (product)