BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This phase 2 study assessed the efficacy of daily oral dosing with everolimus in patients with RCC. METHODS: Patients had confirmed predominantly clear cell RCC; had received ≤1 prior therapy; and had progressive, measurable metastatic disease. Everolimus was given at a dose of 10 mg daily orally without interruption (28‐day cycle), with dose modifications for toxicity (graded according to National Cancer Institute Common Toxicity Criteria, version 3.0). Patients were evaluated every 2 cycles (8 weeks) using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Of 41 enrolled patients, 39 were treated and evaluable for safety, 37 of whom were evaluable for response (2 patients withdrew after the first week of therapy). Approximately 78% of the patients were male, the median age was 60 years, 93% had a Zubrod performance status of 0 to 1, and 83% had received prior therapy. The median progression‐free survival (PFS) was 11.2 months and the median overall survival was 22.1 months. Partial responses were observed in 5 (14%) patients, stable disease lasting ≥3 months was reported in 27 (73%) patients, and stable disease lasting ≥6 months was reported in 21 (57%) patients. Nausea (38% of patients), anorexia (38% of patients), diarrhea (31% of patients), stomatitis (31% of patients), pneumonitis (31% of patients), and rash (26% of patients) were common. Grade 3 of 4 adverse events included pneumonitis (18% of patients); transaminase elevations (10% of patients); thrombocytopenia, hyperglycemia, and alkaline phosphatase elevations (8% each of patients); and hyperlipidemia (5% of patients). CONCLUSIONS: In the current study, everolimus demonstrated encouraging antitumor activity against metastatic RCC as indicated by a PFS ≥ 6 months for approximately 70% of patients. Cancer 2009. © 2009 American Cancer Society.

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5107 Background: RAD001 is an oral mammalian target of Rapamycin (mTOR) inhibitor. Three mechanisms of anti-tumor activity; shuts down tumor response to nutrients and growth factors; cell cycle arrest at late G1 and anti-angiogenesis via VEGF. Molecular alterations in the mTOR modular pathway increase sensitivity in PTEN deficient tumors such as RCC. Endpoints: time-to-progression (TTP), response rate (RR), overall survival (OS), toxicity, and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included; predominant clear cell, progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) = 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 2 cycles (8 weeks). RECIST criteria is utilized. TTP and OS are determined from entry into the study. Results: 41 pts have been enrolled. 37 pts are evaluable for response/toxicity. 2 pts toxicity only. 2 pts screened failures. 31 were male/8 female, median age 60 (38–80) years. 31 pts received prior therapy. 23 pts had a ZPS of 0, 13 /1 and 3/2. Sites of disease included; lung, nodal, liver, bone, adrenal, and kidney. 9 pts had 1 metastatic site, 17 pts/2 and 13 pts/3 or more. 15 pts continue to receive RAD001. 12 pts had partial responses, 19 pts were stable for 3+ months. Median duration of therapy is 8+ (range 01–20+) months. Treatment related adverse events; mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, thrombocytopenia, anemia and elevated LFTs. PET scans have demonstrated decreased metabolic activity in responding or stable pts. Median overall survival is 11.5+ months (range 01–20+). Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC demonstrated by partial response rate. Anti-tumor activity is further suggested by prolonged TTP =3 months. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. An additional 40 pts who failed prior sunitinib or sorafenib therapy are being enrolled. No significant financial relationships to disclose.

4530 Background: RAD001 an oral serine-threonine kinase inhibitor of mTOR, blocks progression from the GI to the S phase of the cell cycle by a mechanism of action that is unique for an anticancer drug. Mechanistically, it is thought that RAD001 may play a role in VEGF inhibition. Main endpoints were to evaluate: time to progression (TTP), response rate, toxicity and to assess changes in metabolic imaging utilizing CT-PET. Methods: Eligibility included: progressive measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤ 2, no more than 1 prior therapy, and no active CNS involvement. RAD001 is given orally at a dose of 10mg daily without an interruption (28-day cycle), with dose modifications for toxicity. Re-evaluation was assessed every 3 cycles (12 weeks). RECIST criteria is utilized to determine response rate. TTP is determined from entry into the study. Results: 25 pts have been enrolled as of this review. 19 male/6 female, range 43–80 (median 60) years. All pts had predominant clear cell elements with progressive MRCC. 17 pts received prior immunotherapy, targeted agents, or chemotherapy. 22 pts had a ZPS of 0, 2/1 and 1/2. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 10 pts/2 metastatic sites and 8 pts/3 or more metastatic sites. 22 pts continue to receive RAD001 therapy. 7 pts had partial responses, 11 pts were stable for 3+ months, (5 pts/6+ months). 4 pts too early. Median duration of therapy is 7+ months (range 1+ to 9+). Treatment related adverse events to date include: mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia and elevated LFTs. Conclusion: RAD001 has promising anti-tumor activity in pts with MRCC as demonstrated by a 33% partial response rate. Anti-tumor activity was further suggested by prolonged TTP ≥ 3 months for 86% of pts. The tumor effect was also demonstrated as a second line therapy. Independent radiology review is planned. Anti-tumor activity, toxicity and metabolic imaging correlation will be presented. [Table: see text]