Phase II Study Shows Activity of Everolimus and Letrozole in Recurrent Endometrial Carcinoma


Key Points

  • Everolimus/letrozole resulted in a 40% clinical benefit rate and a 32% objective response rate.
  • Outcomes were better in patients with endometrioid histology and in those receiving metformin.

Interaction of the estrogen receptor and PI3K/AKT/mTOR pathways and the finding of resistance to hormonal therapy mediated by PI3K activation suggest a benefit of adding an mTOR inhibitor to hormonal treatment in endometrial carcinoma. In a phase II study reported in the Journal of Clinical Oncology, Slomovitz et al found that the combination of the mTOR inhibitor everolimus and the aromatase inhibitor letrozole showed good activity in women with recurrent endometrial cancer.

In this two-institution study, 38 patients (median age, 62 years) who had received no more than two prior cytotoxic regimens were enrolled between May 2010 and September 2011 and treated with everolimus at 10 mg daily and letrozole at 2.5 mg daily in 4-week cycles.


Among 35 evaluable patients, the clinical benefit rate was 40% and the objective response rate was 32% (including complete response in 9 of 11 responders). None of 11 patients with serous histology had clinical benefit or response, whereas clinical benefit and objective response were observed in 14 and 11 of 24 patients with endometrioid histology.

Among five patients with CTNNB1 mutation, four had clinical benefit and three had an objective response. Among nine patients receiving metformin for hyperglycemia present at baseline or developing during the study, six had clinical benefit and five had an objective response (response rate of 56% vs 23% in patients not using metformin, P < .05). At the discretion of the treating clinician, a total of seven patients (20%) were taken off treatment after prolonged complete response.

Adverse Events

The most common treatment-related adverse events of any grade were fatigue (74%), hypertriglyceridemia (74%), hypercholesterolemia (71%), mucositis (66%), anemia (61%), hyperglycemia (55%), and nausea (53%). Everolimus dose reductions were required in 12 patients (32%), due to hyperglycemia in 4, stomatitis in 3, thrombocytopenia in 2, elevated liver function tests in 1, infection in 1, and nausea in 1. No patients required discontinuation of treatment due to toxicity.

The investigators concluded: “Everolimus plus letrozole results in a high [clinical benefit rate] and [objective response rate] in patients with recurrent [endometrial carcinoma]. Further development of this combination in recurrent endometrioid [endometrial carcinoma] is under way.”

Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by a Uterine Specialized Programs of Research Excellence grant, The University of Texas MD Anderson Cancer Center, and Novartis. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.