title: The Pharmacogenetic Rescue of Side-Lined Anticancer Drugs to the Front-Line: Gefitinib as a Case Example.
abstract: OBJECTIVE
  To illustrate the increasing importance of pharmacogenetics in drug development and clinical practice through a critical analysis of the validation and licensing of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as a treatment for non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Journal articles and the "grey" literature were identified through a systematic search of MEDLINE (to June 2010) and the Web sites of the major drug regulators. References identified through the reference lists of major published reviews of gefitinib and Erb receptors, including EGFR, were also reviewed.
  
  
  METHODS
  A broad appraisal of the titles and abstracts of articles on gefitinib and tyrosine kinase inhibitors in lung cancer was undertaken to identify pertinent concepts and relevant publications for further analysis. Articles deemed particularly relevant were retrieved for detailed appraisal. Dossiers on the licensing of gefitinib from the Food and Drug Administration Web site and major published reviews were retrieved. Relevant pharmacogenetic issues were identified and the clinical studies addressing these were evaluated.
  
  
  RESULTS
  Initial promising trial data for gefitinib in NSCLC led to its conditional marketing approval. When the drug's efficacy was not confirmed in a pivotal Phase 3 trial, its prescribing was restricted. Subsequent discovery of activating mutations in the tyrosine kinase domain of EGFR led to further retrospective and prospective evaluation of the drug in patients with those mutations. The new evidence was sufficiently robust to persuade the drug regulators to license the drug as first-line treatment for patients with locally advanced or metastatic NSCLC who test positive for those mutations.
  
  
  CONCLUSIONS
  Pharmacogenetic evidence has played a key role in rescuing gefitinib for front-line treatment of NSCLC. This case-example portends what will be increasingly likely scenarios in the regulation and clinical validation of targeted drug therapies.
authors.affiliation: Alain Li-Wan-Po PhD FRPharmS, Professor, National Genetics Education and Development Centre, Morris House, c/o Birmingham Women's Hospital, Edgbaston, Birmingham, England a.liwanpo@talk21.com.
authors.forename: Alain
authors.initials: A
authors.lastname: Li-Wan-Po
authors.affiliation: Peter A Farndon MSc MD FRCP, Professor and Director, National Genetics Education and Development Centre.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Farndon
authors.affiliation: Susumu Kobayashi MD PhD, Assistant Professor of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Tetsuya Mitsudomi MD, Chief, Department of Thoracic Surgery, Aichi Cancer Centre Hospital, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Vanessa A Potter MBChB PhD FRCP, City Hospital, Consultant Medical Oncologist, Nottingham University Hospitals NHS Trust, Nottingham, England.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Potter
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D011446:Prospective Studies; D011799:Quinazolines / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D018570:Risk Assessment; D018581:Technology Transfer
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib