TPS4678 Background: Everolimus (E), an orally administered mTOR inhibitor, is the conventional agent for progressive disease following vascular endothelial growth factor (VEGF) inhibitors for advanced RCC. Given the excellent tolerability and convenient oral administration, a rationale may be made to develop E as first-line therapy for selected patients. The period between diagnosis and cytoreductive nephrectomy (CN) may be utilized for brief therapy to capture biologic activity in tumor tissue and facilitate individualized systemic therapy. The agent may be resumed following CN and continued until progression. Pharmacodynamic (PD) alterations from baseline to CN tumor tissue may predict progression-free survival (PFS). We hypothesized that the application of this paradigm to E may enable the employment of first-line E in patients predicted to optimally benefit. Methods: This is a 27-patient phase II trial being conducted at the Baylor College of Medicine and University of Texas Southwestern, and 5 patients have been enrolled currently. Patients with ≥3 poor risk factors or those who refuse or are ineligible for VEGF inhibitors and have untreated metastatic RCC are eligible. Adequate hematologic, renal and hepatic function is required. The primary endpoint is PFS and secondary endpoints are response, survival and toxicities. Exploratory endpoints are tumor tissue, peripheral blood mononuclear cell (PBMC) and plasma PD studies and pharmacokinetic (PK) studies, and their association with PFS. PD studies include DNA, mRNA, protein and miRNA studies to evaluate the mTORC1 among other pathways. Patients initially undergo 4 core biopsies of the primary renal mass for fresh frozen tumor. Patients then receive E 10 mg orally once daily for 3-5 weeks. CN is performed within 24-48 hours after the last dose of E. At the time of CN and before separation from the vascular supply, 3 core biopsies are performed. E is resumed 2-4 weeks after CN and continued until progression or intolerable toxicities. Clinical and laboratory assessments are performed every 4-5 weeks, and imaging is performed every 8 weeks. A progressing metastatic site will be biopsied (4 core biopsies).