title: Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma.
abstract: BACKGROUND
  The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib.
  
  
  METHODS
  The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed.
  
  
  CONCLUSIONS
  Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.
authors.affiliation: National Cancer Institute, National Institutes of Health National, Center for Cancer Research , Maryland, USA10 Center Dr, 12N226, Bethesda, MD 20892 , USA +1 301 496 4916 ; +1 301 402 0172 ; mauricio.burottopichun@nih.gov.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Burotto
authors.forename: Syed Abbas
authors.initials: SA
authors.lastname: Ali
authors.forename: Geraldine
authors.initials: G
authors.lastname: O'Sullivan Coyne
mesh_terms: D000077716:Afatinib; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008954:Models, Biological; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib
keywords: afatinib; clinical trial; erlotinib; gefitinib; mutated EGFR; safety; toxicity; tyrosine kinase inhibitor