Phase III Trial of Adjuvant Sunitinib in Patients with High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis

George, Daniel J.; Martini, Jean-Francois; Staehler, Michael; Motzer, Robert J.; Magheli, Ahmed; Donskov, Frede; Escudier, Bernard; Li, Sherry; Casey, Michelle; Valota, Olga; Laguerre, Brigitte; Pantuck, Allan J.; Pandha, Hardev S.; Patel, Anup; Lechuga, Maria und Ravaud, Alain (2019): Phase III Trial of Adjuvant Sunitinib in Patients with High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis. In: Clinical Cancer Research, Bd. 25, Nr. 4: S. 1165-1173

Abstract

Purpose: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between SNPs in several angiogenesis-or hypoxia-related genes and clinical outcomes in S-TRAC. Patients and Methods: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P values were unadjusted. Results: In all, 286 patients (sunitinib, n = 142;placebo, n = 144) were genotyped. Longer DFS [HR;95% confidence inter-val (CI)] was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (HR 0.44;95% CI, 0.21-0.91;P = 0.023), VEGFR2 rs2071559 T/T (HR 0.46;95% CI, 0.23-0.90;P = 0.020), and eNOS rs2070744 T/T (HR 0.53;95% CI, 0.300.94;P = 0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P <= 0.05), and A/A versus C/C with sunitinib (P = 0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P = 0.038) and combined (P = 0.006) groups. Conclusions: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1078-0432
• Sprache: Englisch