title: Genotype Correlations With Blood Pressure and Efficacy From a Randomized Phase III Trial of Second-Line Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma.
abstract: BACKGROUND
  In the phase III axitinib second-line (AXIS) trial, axitinib significantly prolonged progression-free survival (PFS) versus sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Analyses of associations between germline single-nucleotide polymorphisms (SNPs) and outcomes are reported.
  
  
  METHODS
  DNA samples from blood were genotyped using TaqMan allelic discrimination. Logistic/Cox regression analyses were used to evaluate association of 15 SNPs in vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, or hypoxia-inducible factor (HIF)-1α with outcomes for blood pressure (BP; Grade ≥ 3 hypertension, diastolic BP > 90 mm Hg, and increase ≥ 15 mm Hg from baseline) and efficacy (independent review committee-assessed objective response rate and PFS, and overall survival [OS]). Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS and OS.
  
  
  RESULTS
  Genotype data were available for 305 (42.7%) of 714 patients; 159 received axitinib and 146 sorafenib. After Bonferroni adjustment, no SNP was associated with BP outcomes. In axitinib-treated patients, VEGF-A rs699947 (A/A vs. C/C) and rs833061 (C/C vs. T/T) were associated with longer OS (27.0 vs. 13.4 months; hazard ratio [HR], 0.39; Padjusted = .015). In sorafenib-treated patients, VEGFR2 rs2071559 (G/G vs. A/A) was associated with longer OS (26.8 vs. 13.8 months; HR, 0.41; Padjusted = .030). In multivariate analyses, no SNP predicted axitinib efficacy; VEGFR2 rs2071559 predicted PFS (P = .0053) and OS (P = .0027) for sorafenib. Sensitivity/specificity of VEGFR2 rs2071559 for OS was < 80%.
  
  
  CONCLUSIONS
  No SNP predicted axitinib outcomes. Although VEGFR2 rs2071559 predicted sorafenib efficacy in patients with mRCC, sensitivity/specificity limitations preclude its use for selecting individual patients for sorafenib treatment.
authors: Institut Gustave Roussy/Medical Oncology Department, Villejuif, France.
authors: Bernard
authors: B
authors: Escudier
authors: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.
authors: Brian I
authors: BI
authors: Rini
authors: Memorial Sloan Kettering Cancer Center, New York, NY.
authors: Robert J
authors: RJ
authors: Motzer
authors: Pfizer Oncology, San Diego, CA.
authors: Jamal
authors: J
authors: Tarazi
authors: Pfizer Oncology, San Diego, CA.
authors: Sinil
authors: S
authors: Kim
authors: Pfizer Oncology, San Diego, CA.
authors: Xin
authors: X
authors: Huang
authors: Pfizer Oncology, San Diego, CA.
authors: Brad
authors: B
authors: Rosbrook
authors: Pfizer Oncology, San Diego, CA.
authors: Patricia A
authors: PA
authors: English
authors: Pfizer Pharmatherapeutics Precision Medicine, Groton, CT.
authors: A Katrina
authors: AK
authors: Loomis
authors: Pfizer Oncology, San Diego, CA. Electronic address: James.Williams2@pfizer.com.
authors: J Andrew
authors: JA
authors: Williams
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000077784:Axitinib; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D000077157:Sorafenib; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Biomarker; Interpatient; Pharmacogenomic; Single-nucleotide polymorphism