title: Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer.
abstract: BACKGROUND
  We previously reported that progression-free survival (PFS) may be a candidate surrogate end point for overall survival (OS) in first-line extensive-stage small-cell lung cancer (ES-SCLC) using data from three randomized trials (Foster, Cancer 2011). In this validation study (N0424-Alliance), we assessed the patient-level and trial-level surrogacy of PFS using data from seven new first-line phase II/III ES-SCLC trials and across all 10 trials as well (seven new, three previous).
  
  
  METHODS
  Individual patient data were utilized across the seven new trials (2259 patients) and all 10 trials (2855 patients). Patient-level surrogacy (Kendall's τ) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed through association of the log hazard ratios on OS and PFS across trials, including weighted (by trial size) least squares regression (WLS R²) of Cox model effects and correlation of the copula effects (copula R²). The minimum effect on the surrogate (MES) needed to detect a nonzero treatment effect on OS was also calculated.
  
  
  RESULTS
  The median OS and PFS across all 10 trials were 9.8 and 5.9 months, respectively. PFS showed strong surrogacy within the 7 new trials (copula R² = 0.90 [standard error = 0.27], WLS R² = 0.83 [95% confidence interval: 0.43, 0.95]; MES = 0.67, and Kendall's τ = 0.58) and across all 10 trials (copula R² = 0.81 [standard errors = 0.25], WLS R² = 0.77 [95% confidence interval: 0.47-0.91], MES = 0.70, and Kendall's τ = 0.57).
  
  
  CONCLUSIONS
  PFS demonstrated strong surrogacy for OS in first-line ES-SCLC based on this external validation study of individual patient data. PFS is a good alternative end point to OS and should be considered when resource constraints (time or patient) might make it useful or desirable in place of OS. Additional analyses are needed to assess its appropriateness for targeted agents in this disease setting.
authors.affiliation: *Division of Biomedical Statistics and Informatics, Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota; †Department of Radiation Oncology, Mayo Clinic, Scottsdale, Arizona; ‡Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; §Department of Biostatistics and Bioinformatics, Alliance Statistics and Data Center, Duke University, Durham, North Carolina; ‖Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; ¶Department of Oncology, NCIC Clinical Trials Group, Queen' University, Kingston, ON, Canada; #Department of Hematology & Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia; **Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California; ††Department of Statistics for the Data Center/Operations Office, Japan Clinical Oncology Group Data Center, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan; ‡‡Department of Medical Oncology, Japanese Society of Medical Oncology, Tokyo, Japan; §§Department of Medicine, The University of Chicago Medicine and Biologic Sciences Center, Chicago, Illinois; and ‖‖Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Renfro
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: Mary W
authors.initials: MW
authors.lastname: Redman
authors.forename: Xiaofei F
authors.initials: XF
authors.lastname: Wang
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Bradbury
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.forename: Taro
authors.initials: T
authors.lastname: Shibata
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D018572:Disease-Free Survival; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D055752:Small Cell Lung Carcinoma / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D055815:Young Adult