Background: Temsirolimus and everolimus are standard agents in the management of advanced renal cell carcinoma, but the registration trials primarily enrolled patients with clear cell histology. We assessed outcome in patients with non-clear cell RCC (ncRCC) treated with mTOR inhibitors at our center. Methods: Clinical features and histologic subtypes were characterized for ncRCC patients treated with single-agent temsirolimus or everolimus. Outcome was analyzed using the Kaplan-Meier method to determine progression free survival (PFS) and overall survival (OS). Genomic analysis of outliers with either durable or poor response was done by next-generation sequence analysis of tumor tissue and germline DNA. Results: 65 patients received temsirolimus (n = 46) or everolimus (n = 19). Histologic subtypes included papillary (n = 16), chromophobe (n = 9), collecting duct (n = 6), translocation-associated (n = 3), and unclassified (n = 31) RCC. Median follow-up for survivors is 29 mos. Median treatment duration for 52 patients, who continue therapy or stopped due to progression or death, is 2 mos. 8 patients (12.3%) were treated for ≥ 1 year (max. 37 mos), including papillary (n = 3), chromophobe (n = 2) and unclassified (n = 3) RCC. Tumor analysis identified genomic determinants of long term response in 2 unclassified RCC (complete functional loss of TSC1 and TSC2, respectively). No such changes were seen in 2 patients with chromophobe RCC and rapid progression on therapy. Conclusions: A subset of ncRCC patients derives benefit from mTOR inhibitors, but most have poor outcome. Durable responses can be linked to oncogenomic alterations within the mTOR pathway, and future goals should include the identification and characterization of such predictive tissue biomarkers.

*LDH not available for 1 patient.