A Phase 2 Study of the Oral Mammalian Target of Rapamycin Inhibitor, Everolimus, in Patients With Recurrent Endometrial Carcinoma

BACKGROUND: Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110 alpha catalytic subunit of phosphatidylinosito1-3-kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up-regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR. METHODS: A single-institution, open-labeled, phase 2 study of everolimus in patients with measurable recurrent EC who had failed at least 1 and no more than 2 prior chemotherapeutic regimens was performed. Everolimus was administered at a dose of 10 mg orally daily for 28-day cycles. Patients were treated until disease progression or toxicity. The primary endpoint was clinical benefit response (CBR), defined as a confirmed complete or partial response or prolonged stable disease (SD) (>= 8 weeks). Inclusion was limited to patients with endometrioid histology. RESULTS: A total of 35 patients were enrolled (median age, 58 years; range, 38-81 years). A total of 81 cycles were administered. Twelve of 28 (43%) evaluable patients had not developed disease progression at the time of the first objective evaluation (8 weeks). All these patients had SD (median, 4.5 cycles; range, 2-10 cycles). Six of the 28 (21%) patients had a confirmed CBR at 20 weeks of therapy. Patients with CBR discontinued treatment because of toxicity (6 patients), disease progression (5 patients), and noncompliance (1 patient). Seven patients were unevaluable after receiving <= 1 cycle because of toxicity (5 patients) or noncompliance (2 patients). The most common drug-related toxicities were fatigue, anemia, pain, lymphopenia, and nausea. CONCLUSIONS: Everolimus demonstrated encouraging single-agent CBR in pretreated patients with recurrent endometrioid EC. Future studies will evaluate this agent in combination with hormonal and/or cytotoxic therapy. Cancer 2010;116:5415-9. (C) 2010 American Cancer Society.