Maxine Sun, Alessandro Larcher, Pierre I Karakiewicz

Since 2005, an abundance of targeted agents has been approved for the treatment of metastatic renal cell carcinoma (mRCC), without any specification as to what may be the most optimal first-line and second-line sequence. Hence, our objective was to critically examine the evidence supporting the use of first-line and second-line agents in the management of mRCC. Our review suggests that in first line, sunitinib and pazopanib represent treatment options for patients with favorable or intermediate-risk features and clear cell histology. Unfortunately, the Phase III trial cannot conclusively prove the noninferiority of pazopanib relative to sunitinib. Hence, the use of sunitinib as first-line standard of care remains justified. Pazopanib represents an option for specific patients in whom sunitinib might not be tolerated. In patients with poor-risk features, temsirolimus represents the only option supported with level 1 evidence. Less optimal alternatives include sunitinib and bevacizumab combined with interferon, based on the minimal inclusion of poor-risk patients in pivotal Phase III studies of these two molecules. In patients with non-clear cell mRCC, the use of temsirolimus is supported by Phase III data, unlike for any other molecule. In second line, the options consist of everolimus and axitinib. However, the axitinib data are substantially more robust given the inclusion of more patients considered as true second-line, and validly justify the choice of axitinib over everolimus. Nonetheless, the Phase III trial of everolimus may be considered as level 1 evidence for use as third-line or subsequent lines of therapy.