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5567 Background: Hormonal therapy has limited activity in gynecologic (Gyn) cancer treatment. mTOR inhibitors plus aromatase inhibitors (AI's) improve the response rate and response duration in breast cancer patients. We studied this combination in heavily pre-treated women having estrogen receptor positive (ER+) Gyn cancers. Methods: This phase II study combines everolimus and letrozole for ER+ Gyn cancers with disease progression following primary and salvage chemotherapy. 19 patients participated (Ovary-10, Endometrium-7, and Primary Peritoneal Cancer-2). The mean age was 64, prior lines of therapy ranged from 2-7, and median time from diagnosis to study entry was 67 months (m) (range 10-348m). Results: There were no complete responders, but 7 of 19 (37%) patients treated had clinical benefit, with 1 PR and 6 with stable disease. In responding patients, the earliest time to best response was 2m and the median time to progression was 5m (range 5-40+m). The mean number of treatment cycles was 11. Toxicities: The most common adverse events were: hyperglycemia, rash, stomatitis, fatigue, and anemia. 7 patients required dose reductions, and 2 discontinued study drugs due to pneumonitis. The therapy was generally well tolerated in both women < 65 and > 65 years old. Toxicities were less common with reduced everolimus doses. Conclusions: Recurrent Gyn cancers become refractory to chemotherapy. We tested the combination of everolimus plus letrozole in heavily pretreated patients with ER + recurrent disease. 1 patient had a PR and 6 had stable disease with a range of 5-40+m. This oral regimen was generally well tolerated and allowed time without IV chemotherapy, while providing clinical benefit to patients with refractory ER+ Gyn cancers.