title: Endpoints in phase II trials for advanced non-small cell lung cancer.
abstract: BACKGROUND
  We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer.
  
  
  METHODS
  Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index).
  
  
  RESULTS
  The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59-0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes.
  
  
  CONCLUSIONS
  FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.
authors.affiliation: Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA. mandrekar.sumithra@mayo.edu
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Qi
authors.forename: Shauna L
authors.initials: SL
authors.lastname: Hillman
authors.forename: Katie L
authors.initials: KL
authors.lastname: Allen Ziegler
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Reuter
authors.forename: Kendrith M
authors.initials: KM
authors.lastname: Rowland
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kuross
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Marks
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000628:therapy*; D017322:Clinical Trials, Phase II as Topic; D003131:Combined Modality Therapy; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome