OBJECTIVES: Patients with mRCC and a good performance status typically receive an anti-VEGFR TKI (sunitinib or pazopanib) as initial therapy.  Upon disease progression or intolerance, there are four orally-administered agents approved in the 2nd - line setting (including cytokine-refractory).  However, head to head comparative trial data are limited.  In the absence of such data, mixed treatment comparison (MTC) models are a widely accepted statistical method for generating comparative effectiveness information.  In this study, an indirect comparison on the safety and efficacy was undertaken between axitinib, sorafenib, pazopanib and everolimus for 2nd - line therapy in advanced RCC. METHODS: A systematic review of major databases was conducted from January 2005 to June 2013 for randomized controlled trials evaluating at least one of the four agents in 2nd- line mRCC.  Bayesian MTC models were fitted to assess comparative effectiveness based on multiple endpoints: tumour response, progression free survival (PFS), grade III/IV toxicities such as diarrhea, fatigue, hand foot skin reaction, rash and stomatitis as well as treatment discontinuations. RESULTS: A total of four randomized trials meeting the inclusion criteria were appropriate for the statistical pooling exercise.  All four agents seem able to induce tumour shrinkage and provide patients with a clinically meaningful PFS benefit.  Axitinib was superior to pazopanib (HR = 0.64; 95%Crl: 0.42 to 0.96) and sorafenib (HR = 0.70; 95%Crl: 0.57 to 0.87) in terms of PFS. However, patients receiving axitinib would be at an elevated risk for fatigue and to a lesser extent, stomatitis. CONCLUSIONS: Keeping in the mind the caveats associated with cross-trial comparisons, axitinib appears to provide superior PFS benefits relative to pazopanib and sorafenib.  However, this is at a cost of a higher frequency of some dose-limiting toxicities.  Everolimus, an mTor inhibitor, is mechanistically distinct from the other agents evaluated and would be a useful option post anti-VEGFR TKI failure.