title: Efficacy and Safety of Selective Vascular Endothelial Growth Factor Receptor Inhibitors Compared with Sorafenib for Metastatic Renal Cell Carcinoma: a Meta-analysis of Randomised Controlled Trials.
abstract: OBJECTIVE
  Selective vascular endothelial growth factor receptor (VEGFR) inhibitors have the potential for greater potency and less off-target toxicity compared with multikinase tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma. We carried out a meta-analysis to determine quantitatively the differences in comparative efficacy and tolerability between these newer, selective agents and the multikinase inhibitors.
  
  
  METHODS
  We searched four electronic databases for published randomised controlled trials comparing selective VEGFR inhibitors with multikinase tyrosine kinase inhibitors for metastatic renal cell carcinoma and carried out a meta-analysis. Outcomes of interest were progression-free survival, objective response rate (ORR), overall survival, discontinuation of treatment due to adverse events (DAE) and occurrence of specific toxicities.
  
  
  RESULTS
  Four trials involving the selective VEGFR inhibitors axitinib, tivozanib and dovitinib were analysed, all using sorafenib as the comparator. There was a 22% reduction in risk of disease progression with selective VEGFR inhibitors (relative risk 0.78; 95% confidence interval 0.69-0.87) compared with sorafenib, the tyrosine kinase inhibitor in all trials, and similar whether the agents were first-line or subsequent therapy. ORR was improved with selective VEGFR inhibitors, with 91% increased odds over sorafenib (odds ratio 1.91; 95% confidence interval 1.35-2.69). Overall survival was similar between groups (relative risk 1.03; 95% confidence interval 0.88-1.21) and DAE differed only in sensitivity analysis with exclusion of dovitinib (odds ratio 0.62; 95% confidence interval 0.41-0.94). Frequencies of the most common toxicities were overall similar, but differences included more frequent grade 3 or 4 fatigue and less frequent palmar-plantar erythrodysesthesia with selective VEGFR therapy.
  
  
  CONCLUSIONS
  Although selective VEGFR inhibitors are associated with similar overall survival as multikinase inhibitor sorafenib, they show significant improvement in progression-free survival, regardless of first-line or later use, and ORR compared with sorafenib. Tolerability due to toxicities is similar.
authors.affiliation: New York University Medical Center, Department of Radiology, New York, New York, USA; New York University Medical Center, Department of Population Health, New York, New York, USA. Electronic address: stella.kang@nyumc.org.
authors.forename: S K
authors.initials: SK
authors.lastname: Kang
authors.affiliation: North Shore University Hospital, Department of Cardiology, Manhasset, New York, USA.
authors.forename: A
authors.initials: A
authors.lastname: Volodarskiy
authors.affiliation: New York University Medical Center, Department of Urology, New York, New York, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Ohmann
authors.affiliation: New York University Medical Center, Department of Medicine, New York, New York, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Balar
authors.affiliation: New York University Medical Center, Department of Medicine, New York, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bangalore
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077784:Axitinib; D001562:Benzimidazoles / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007191:Indazoles / Q000008:administration & dosage; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D011804:Quinolines / Q000008:administration & dosage; D015363:Quinolones / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D011804:Quinolines; D015363:Quinolones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C553176:tivozanib; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib
keywords: Meta-analysis; renal cell carcinoma; targeted therapy; tyrosine kinase inhibitor