Abstract LB-78: Pharmacogenomic analysis of a phase III trial of gemcitabine/axitinib versus gemcitabine/placebo in patients with advanced pancreatic cancer

Abstract

Abstract Background: The oral antiangiogenic agent axitinib (AG-013736) is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3. We explored potential associations between germline single nucleotide polymorphisms (SNPs) in genes regulating angiogenesis and response to axitinib in pts with advanced pancreatic cancer. In a previous Phase III study of pts with advanced breast cancer treated with bevacizumab, VEGF-2578 (rs699947) AA genotype was associated with increased overall survival (OS). A VEGFR1 SNP (rs9582036) has also been associated with OS in pts with metastatic pancreatic cancer who received bevacizumab. Methods: This analysis was based on a double-blind Phase III trial of pts with metastatic or locally advanced nonresectable pancreatic adenocarcinoma who were randomized 1:1 to gemcitabine 1000 mg/m2 + axitinib 5 mg twice daily (n=316) or gemcitabine + placebo (n=316). Twelve angiogenesis-related SNPs were analyzed including VEGFA, VEGFR1, VEGFR2, HIF1A, and WHSC2 using DNA isolated from peripheral blood samples. All 12 SNPs were analyzed for associations with OS. The 5 VEGFA SNPs (rs699947, rs1570360, rs833061, rs2010963, rs3025039) were also examined for possible relationships with OS, hypertension (Grade ≥3), and blood pressure (BP; at least 1 measurement of diastolic BP ≥90 mmHg during treatment). This analysis focused on the Caucasian subpopulation (68% of total). Results: Of the 632 pts, 301 voluntarily donated blood samples for genotyping. Most samples evaluable for association analyses (as-treated population) came from Caucasians (260/297, 88%). Among the subpopulation of pts who consented to genotyping, significantly more had metastatic disease than locally advanced disease compared with those who did not consent (238/59 vs 241/92; P=0.0249). Pts with available genotyping data had a correspondingly shorter OS (median OS 7.15 mo vs 9.48 mo; P=0.0068). The genotyped pts had a significantly lower ratio of Asian to Caucasian pts (22/260 vs 151/171; P=2.2×10-16). No significant correlations were found between any of the SNPs examined and OS. Furthermore, no associations were noted between the VEGFA SNPs and either hypertension or high BP. Conclusions: No statistically significant associations were seen between examined SNPs and clinical end points in pts with advanced pancreatic cancer treated with gemcitabine/axitinib. Owing to differences in baseline demographics and stratification factors between the genotyped and nongenotyped pts, these results cannot be extrapolated beyond this subpopulation. This pharmacogenomic component demonstrated that it is feasible to collect donated samples from nearly 50% of pts in a large international Phase III trial. Further studies will examine possible associations between VEGFA SNPs or other polymorphisms and clinical outcomes in VEGF-driven tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-78.