Phase Ib/II study of LEE011, everolimus, and exemestane in postmenopausal women with ER+/HER2-metastatic breast cancer.

535 Background: Aromatase inhibitors (AIs) are the recommended first-line endocrine therapy for postmenopausal (PM) patients (pts) with ER+/HER2– advanced/metastatic breast cancer (aBC). However, resistance develops over time. Activation of the PI3K/AKT/mTOR pathway and downstream cyclin D–cyclin-dependent kinase (CDK4/6) has been implicated in endocrine-therapy resistance. Combination of the mTOR inhibitor everolimus (EVE) with exemestane (EXE) significantly improved PFS of pts with ER+/HER2– aBC (BOLERO-2), and preclinical data suggest that combination of EXE, EVE, and the CDK4/6 inhibitor LEE011 may be even more effective in endocrine-resistant ER+/HER2– BC. Methods: During Phase (Ph) Ib, PM pts with ER+/HER2– aBC are being treated with escalating doses of LEE011 (3 wks on/1 wk off), EVE (continuous), and a fixed daily dose of EXE (25 mg/d; continuous; arm 1); or with a safety run-in of LEE011 (600 mg/d; 3 wks on/1 wk off) and EXE (25 mg/d; continuous; arm 2) to confirm the recommended Ph II dose (RP2D...