title: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.
abstract: OBJECTIVE
  Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting.
  
  
  METHODS
  Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351).
  
  
  RESULTS
  PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation.
  
  
  CONCLUSIONS
  Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.
authors.affiliation: Department of Thoracic Oncology, Hospital Grosshansdorf, Wohrendamm 80, 22927 Grosshansdorf, Germany. dr.martin.reck@web.de
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.forename: Petr
authors.initials: P
authors.lastname: Zatloukal
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbounova
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.forename: Jörg
authors.initials: J
authors.lastname: Mezger
authors.forename: Venice
authors.initials: V
authors.lastname: Archer
authors.forename: Nicola
authors.initials: N
authors.lastname: Moore
authors.forename: Christian
authors.initials: C
authors.lastname: Manegold
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D000068258:Bevacizumab; D002945:Cisplatin; D000093542:Gemcitabine