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.
Keywords: Angiogenesis; Biomarker; Interpatient; Pharmacogenomic; Single-nucleotide polymorphism.
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