Background: We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods: A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results: We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71 male, favourable risk 16 , intermediate risk 84 . Cycle 2 commenced within 14 weeks for 80 of participants; 64 received =22 weeks of alternating therapy; 78 received =22 weeks of any treatment. PFS6m was 29/55 (53 ; 95 confidence interval [CI] 40 to 66 ). Tumour response rate was 7/55 (13 ; 95 CI 4 to 22 , all partial responses). After median follow-up of 20 months, 47 of 55 (86 ) had progressed with a median progression-free survival of 8 months (95 CI 5-10), and 30 of 55 (55 ) had died with a median OS of 17 months (95 CI 12-undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions: The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.