title: Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial.
abstract: OBJECTIVE
  To compare the efficacy of aflibercept (ziv-aflibercept), a recombinant human fusion protein targeting the vascular endothelial growth factor (VEGF) pathway, with or without docetaxel in platinum-pretreated patients with advanced or metastatic nonsquamous non-small-cell lung cancer.
  
  
  METHODS
  In this international, double-blind, placebo-controlled phase III trial, 913 patients were randomly assigned to (ziv-)aflibercept 6 mg/kg intravenous (IV; n = 456) or IV placebo (n = 457), both administered every 3 weeks and in combination with docetaxel 75 mg/m(2). The primary end point was overall survival (OS). Other efficacy outcomes, safety, and immunogenicity were also assessed.
  
  
  RESULTS
  Patient characteristics were balanced between arms; 12.3% of patients had received prior bevacizumab. (Ziv-)Aflibercept did not improve OS (hazard ratio [HR], 1.01; 95% CI, 0.87 to 1.17; stratified log-rank P = .90). The median OS was 10.1 months (95% CI, 9.2 to 11.6 months) for (ziv-)aflibercept and 10.4 months (95% CI, 9.2 to 11.9 months) for placebo. In exploratory analyses, median progression-free survival was 5.2 months (95% CI, 4.4 to 5.6 months) for (ziv-)aflibercept versus 4.1 months (95% CI, 3.5 to 4.3 months) for placebo (HR, 0.82; 95% CI, 0.72 to 0.94; P = .0035); overall response rate was 23.3% of evaluable patients (95% CI, 19.1% to 27.4%) in the (ziv-)aflibercept arm versus 8.9% (95% CI, 6.1% to 11.6%; P < .001) in the placebo arm. Grade ≥ 3 adverse events occurring more frequently in the (ziv-)aflibercept arm versus the placebo arm were neutropenia (28.0% v 21.1%, respectively), fatigue (11.1% v 4.2%, respectively), stomatitis (8.8% v 0.7%, respectively), and hypertension (7.3% v 0.9%, respectively).
  
  
  CONCLUSIONS
  The addition of (ziv-)aflibercept to standard docetaxel therapy did not improve OS. In exploratory analyses, secondary efficacy end points did seem to be improved in the (ziv-)aflibercept arm. The study regimen was associated with increased toxicities, consistent with known anti-VEGF and chemotherapy-induced events.
authors.affiliation: Wielkopolskie Centrum Pulmonologii i Torakochirurgii, Poznań University of Medical Sciences, Augustyna Szamarzewskiego 62, 61-001 Poznań, Poland. rramlau@onet.eu
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.forename: Tudor Eliade
authors.initials: TE
authors.lastname: Ciuleanu
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ozguroglu
authors.forename: Tuncay
authors.initials: T
authors.lastname: Goksel
authors.forename: Clarissa
authors.initials: C
authors.lastname: Baldotto
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Solenn
authors.initials: S
authors.lastname: Le-Guennec
authors.forename: Augustin
authors.initials: A
authors.lastname: Rey
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.forename: Nicholas
authors.initials: N
authors.lastname: Thatcher
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D016001:Confidence Intervals; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D010984:Platinum / Q000627:therapeutic use; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D018570:Risk Assessment; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D011993:Recombinant Fusion Proteins; D043823:Taxoids; C533178:aflibercept; D000077143:Docetaxel; D010984:Platinum; D040262:Receptors, Vascular Endothelial Growth Factor