Clinical experience and critical evaluation of the role of everolimus in advanced renal cell carcinoma

Maxine Sun1, Firas Abdollah2, Jan Schmitges1, Claudio Jeldres1, Shahrokh F Shariat3, Paul Perrotte4, Pierre I Karakiewicz1,4 1Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada; 2Department of Urology, Vita Salute San Raffaele University, Milan, Italy; 3Department of Urology, Weill Medical College of Cornell University, New York, NY, USA; 4Department of Urology, University of Montreal Health Center, Montreal, CanadaAbstract: The efficacy of sequential everolimus, an orally administered inhibitor of mammalian target of rapamycin (mTOR), was proven in a placebo-controlled phase III study, where median progression-free survival was 4.9 vs 1.9 months for placebo (hazard ratio: 0.33, P < 0.001). Placebo crossovers (80%) contaminated overall survival data. Adverse event discontinuation rate was of only 10% and health-adjusted quality-of-life was sustained. These data represent the first placebo-controlled evidence of efficacy for a seque ntially used targeted agent. Everolimus resulted in the strongest hazard ratio ever recorded for progression-free survival, despite it being tested in a population with the most aggressive natural history ever recorded in all available phase III metastatic renal cell carcinoma trials. Everolimus use after exclusively one prior antivascular endothelial growth factor f ailure resulted in an even longer progression-free survival time (5.4 months) than in the entire population (4.9 months). These benefits should also be considered in the light of sustained and unimpaired health-related quality of life. Use in first line other than second or subsequent lines remains to be validated.Keywords: everolimus, metastatic renal cell carcinoma, targeted therapy, sequential therapy, mTOR