Background:The mammalian target of rapamycin (mTOR) is an important therapeutic target in the treatment of renal cell carcinoma (RCC). Pre-clinical data indicate that the combined inhibition of both the epidermal growth factor receptor and mTOR results in enhanced anticancer activity.Methods:All patients had metastatic RCC with progression after treatment with sunitinib and/or sorafenib. Treatment consisted of erlotinib 150 mg orally once a day starting on day 1 and sirolimus >6 mg orally on day 8 followed by 2 mg daily, adjusted according to blood levels.Results:A total of 25 patients were enrolled between July 2006 and March 2008. The median progression-free survival (PFS) was 12 weeks (95% CI 5.9-18.1) and median overall survival (OS) 40 weeks (95% CI 0-85.7). No confirmed complete or partial responses were observed, but stable disease 6 months was noted in 21.8% (95% CI 4.9-38.6) of patients. The most common adverse events were rash and diarrhoea. There was no correlation between erlotinib, OSI-420 (days 8 and 15) or sirolimus (days 15 and 29) blood levels and PFS or OS.Conclusions:The combination of sirolimus and erlotinib for RCC failed to demonstrate an advantage over available single-agent therapy in the second-line setting. © 2010 Cancer Research UK All rights reserved.