A Phase II Open Label Study of Everolimus in Combination with Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

Abstract Background Therapies targeting estrogen receptor signaling are standard for patients with hormone receptor positive (HR+) metastatic breast cancer (MBC). Dysregulation of the PI3K/AKT/mTOR pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled PFS in HR+/HER2− MBC patients who previously progressed on endocrine therapy. In this phase II study, we added everolimus to the most recent endocrine therapy on which a patient progressed, in an attempt to restore and extend the benefit of the anti-estrogen therapy in patients with HR+/HER2- MBC. Methods Patients with HR+ MBC who had progressed on anti-estrogen therapy received everolimus (10 mg PO daily) in combination with the anti-estrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat and Foundation One® assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, alpha 5%). Results Forty-seven patients were enrolled and treated. After a median follow up of 22.2 months, median PFS was 6.6 months. Secondary efficacy endpoints included: overall response rate 6%, clinical benefit rate 40%, median OS 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat prognostic signatures. Conclusion Following progression on anti-estrogen therapy, addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR+/HER2- MBC.