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Proton pump inhibitors (PPIs) can affect optimal absorption of concomitant oral cancer treatments. We conducted a pooled analysis to investigate the effect of PPI use in 2188 metastatic renal cell carcinoma patients treated with oral targeted therapy. Survival outcomes were similar between PPI users and nonusers. Our data highlight the importance of anticipating risks associated with polypharmacy in patients who receive oral targeted therapy.Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and can affect the optimal absorption of concomitant oral medications, such as vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs). The purpose of this study was to investigate the effect of PPI use on survival in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era.We conducted a pooled analysis of mRCC patients treated in phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan–Meier method.We identified 2188 patients treated with sunitinib (n = 952), axitinib (n = 626) or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users showed similar overall survival compared with non-PPI users (hazard ratio [HR], 1.051; 95% confidence interval [CI], 0.769-1.438; P = .754; median, 24.1 vs. 21.3 months). Similarly, progression-free survival (HR, 1.016; 95% CI, 0.793-1.301; P = .902; median, 5.5 vs. 8.0 months) and objective response rates (23.3% vs. 27.4%; P = .344) were not different between PPI users and nonusers. These findings were consistent across International mRCC Database Consortium risk groups and according to line of therapy. Adverse events were similar between PPI users and nonusers.We showed that PPI use does not appear to negatively affect the efficacy and safety of select VEGF-TKIs in patients with mRCC. Documentation of concomitant medications and patient education on potential drug interactions are critical for optimizing the use of oral cancer-targeting therapy.