title: Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial.
  
  
  METHODS
  In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728.
  
  
  RESULTS
  Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80-1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1-21·6) for patients in the bevacizumab group compared with 9·2 months (3·8-20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4-8·4]) than in the control group (1·7 months [1·3-4·1]; HR 0·62, 95% CI 0·52-0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group.
  
  
  CONCLUSIONS
  Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC.
  
  
  BACKGROUND
  Genentech.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA. roy.herbst@yale.edu
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: Rafat
authors.initials: R
authors.lastname: Ansari
authors.forename: Frederique
authors.initials: F
authors.lastname: Bustin
authors.forename: Patrick
authors.initials: P
authors.lastname: Flynn
authors.forename: Lowell
authors.initials: L
authors.lastname: Hart
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Otterson
authors.forename: Gordana
authors.initials: G
authors.lastname: Vlahovic
authors.forename: Chang-Heok
authors.initials: CH
authors.lastname: Soh
authors.forename: Paula
authors.initials: P
authors.lastname: O'Connor
authors.forename: John
authors.initials: J
authors.lastname: Hainsworth
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride