title: Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review.
abstract: BACKGROUND
  In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed.
  
  
  RESULTS
  We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%.
  
  
  CONCLUSIONS
  The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Hospital Division and the University of Toronto, Toronto, Ontario, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.affiliation: National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Rabab Mohamed
authors.initials: RM
authors.lastname: Gaafar
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Kayatani
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tabata
authors.affiliation: Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan.
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D016017:Odds Ratio; D018579:Patient Selection; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors