title: Dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in the treatment of advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  The strategy of dual inhibiting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways has been extensively investigated in advanced non-small-cell lung cancer (NSCLC), but the benefit-to-risk ratio of dual-targeted regimen versus EGFR-tyrosine kinase inhibitors (TKIs) alone is still unclear. We thus perform this meta-analysis to assess the efficacy and safety of this regimen versus EGFR-TKIs alone in those patients.
  
  
  METHODS
  Databases from PubMed, Web of Science and the Cochrane Library up to March 31, 2015 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating dual inhibiting EGFR and VEGF pathways versus EGFR-TKIs alone in advanced NSCLC. The endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and grade 3 or 4 adverse events. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies.
  
  
  RESULTS
  A total of 1918 patients with advanced NSCLC from 4 RCTs were identified for the analysis. The pooled results demonstrated that dual inhibiting EGFR and VEGF pathways significantly improved the PFS (HR 0.71, 95 % CI 0.58-0.86, p < 0.001) and ORR (OR 1.54, 95 % CI 1.14-2.08, p = 0.005) in unselected NSCLC when compared to EGFR-TKIs alone, but it did not translate into OS benefit (HR 0.94, 95 % CI 0.84-1.05, p = 0.24). No evidence of publication bias was observed.
  
  
  CONCLUSIONS
  Our study suggests that dual inhibition of EGFR and VEGF pathways significantly improves PFS and ORR, but it does not translate into survival benefit in unselected NSCLC patients. Prospective clinical trials investigating the role of this regimen in EGFR mutation-positive NSCLC are still warranted.
authors.affiliation: Department of Oncology, The First People's Hospital of Shangqiu, No. 292, South Kaixuan road, Shangqiu, 476100, Henan, China.
authors.forename: T T
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The First People's Hospital of Shangqiu, No. 292, South Kaixuan road, Shangqiu, 476100, Henan, China.
authors.forename: R M
authors.initials: RM
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East jian she road, Zhengzhou, 450052, Henan, China. zhenyang20150606@163.com.
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Oncology, The First People's Hospital of Shangqiu, No. 292, South Kaixuan road, Shangqiu, 476100, Henan, China. chengongbin2015@163.com.
authors.forename: G B
authors.initials: GB
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Angiogenesis inhibitors; EGFR-TKIs; Meta-analysis; Molecular targeted agents; Non-small-cell lung cancer