title: Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.
abstract: OBJECTIVE
  Treatment of patients with oncogene-addicted cancers with tyrosine kinase inhibitors (TKI) is biologically and clinically different than with cytotoxic chemotherapy. We have observed that some patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib (RECIST progression after initial benefit) have accelerated progression of disease after discontinuation of TKI. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib.
  
  
  METHODS
  We evaluated patients with EGFR-mutant lung cancer who participated in trials for patients with acquired resistance that mandated TKI discontinuation before administration of study therapy. Disease flare was defined as hospitalization or death attributable to disease progression during the washout period.
  
  
  RESULTS
  Fourteen of 61 patients (23%; 95% CI: 14-35) experienced a disease flare. The median time to disease flare after TKI discontinuation was 8 days (range 3-21). Factors associated with disease flare included shorter time to progression on initial TKI (P = 0.002) and the presence of pleural (P = 0.03) or CNS disease (P = 0.01). There was no association between disease flare and the presence of T790M at the time of acquired resistance.
  
  
  CONCLUSIONS
  In patients with EGFR-mutant lung cancer and acquired resistance to epidermal growth factor receptor TKIs, discontinuation of erlotinib or gefitinib before initiation of study treatment is associated with a clinically significant risk of accelerated disease progression. Clinical trials in this patient population must minimize protocol-mandated washout periods.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Chaft
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Oxnard
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D013997:Time Factors; D028761:Withholding Treatment
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib