title: Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non-small-cell lung cancer: the bar is dropping.
abstract: OBJECTIVE
  Despite multiple trials of new agents in advanced non-small-cell lung cancer (NSCLC), outcomes remain poor. This study explores how the design and interpretation of randomized trials in advanced NSCLC has changed over time.
  
  
  METHODS
  Phase III randomized controlled trials of systemic therapy for advanced NSCLC between 1980 and 2010 were identified, and their primary end point, outcome, statistical significance, and conclusions were recorded.
  
  
  RESULTS
  Of 245 trials identified, 203 were eligible for study inclusion. Although overall survival remains the most common primary end point of phase III trials, more trials from the last decade have used progression-free survival instead (none in 1980 to 1990, 13% in 2001 to 2010; P = .002). The percentage of trials meeting their primary statistical end points remained stable over time; however, the percentage of trials reporting a positive outcome without meeting that end point increased (30% in 1980 to 1990, 53% in 2001 to 2010; P < .001). A trend toward decreasing magnitude of survival gain in positive trials was seen over time (3.9 months in 1980 to 1990, 2.5 months in 2001 to 2010; P = .11), with a concomitant increase in the sample size of clinical trials over the same time period (median: 152 patients in 1980 to 1990, 413 in 2001 to 2010; P < .001). Only studies predating 1990 reported negative results as a result of insufficient magnitude of survival benefit despite statistical significance.
  
  
  CONCLUSIONS
  A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced NSCLC. The use of survival as the primary measure of benefit is declining, as is the magnitude of benefit deemed clinically relevant.
authors.affiliation: All authors: Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Sacher
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Le
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic / Q000592:standards / Q000639:trends*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D012107:Research Design / Q000592:standards / Q000639:trends*; D016896:Treatment Outcome