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.

PATIENTS AND 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%.

CONCLUSION:

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: Bernard Escudier, Brian I Rini, Robert J Motzer, Jamal Tarazi, Sinil Kim, Xin Huang, Brad Rosbrook, Patricia A English, A Katrina Loomis, J Andrew Williams
• Journal: Clinical genitourinary cancer (Clin Genitourin Cancer) Vol. 13 Issue 4 Pg. 328-337.e3 (Aug 2015) ISSN: 1938-0682 [Electronic] United States
• PMID: 25816720 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Imidazoles
• Indazoles
• Phenylurea Compounds
• Niacinamide
• Sorafenib
• Axitinib
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Aged
• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Axitinib
• Blood Pressure (drug effects, genetics)
• Carcinoma, Renal Cell (drug therapy, genetics, mortality, physiopathology)
• Disease-Free Survival
• Female
• Genetic Association Studies
• Humans
• Imidazoles (pharmacology, therapeutic use)
• Indazoles (pharmacology, therapeutic use)
• Kaplan-Meier Estimate
• Kidney Neoplasms (drug therapy, genetics, mortality, physiopathology)
• Linkage Disequilibrium
• Male
• Middle Aged
• Multivariate Analysis
• Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Polymorphism, Single Nucleotide
• Proportional Hazards Models
• Sorafenib
• Vascular Endothelial Growth Factor Receptor-1 (genetics)
• Vascular Endothelial Growth Factor Receptor-2 (genetics)