title: The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small-cell lung cancers: A meta-analysis of randomized trials.
abstract: The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy.
  
  
  
  We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology.
  
  
  
  The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI.
  
  
  
  The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Bob T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Tristan A
authors.initials: TA
authors.lastname: Barnes
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Chan
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 301 Building Suite 4500, Baltimore, MD 21224, USA.
authors.forename: Jarushka
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Lee
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Khasraw
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; SAN Integrated Cancer Centre, Sydney Adventist Hospital, 185 Fox Valley Rd, Wahroonga, NSW 2076, Australia.
authors.forename: Gavin M
authors.initials: GM
authors.lastname: Marx
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clarke
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Electronic address: nick.pavlakis@sydney.edu.au.
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Angiogenesis; lung cancer; meta-analysis; tyrosine kinase inhibitors