A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor Positive Metastatic Breast Cancer

Purpose:Phosphatidylinositol-3-kinase (PI3K)/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen-deprivation or fulvestrant, we conducted a Phase 1 trial in patients with metastatic ER+HER2- breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant. Experimental Design:ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen-deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined based on toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, and fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results:MK-2206 induced apoptosis in parental ER+ but not in long term estrogen deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty one patients enrolled. The RPTD was defined as MK-2206 150 mg PO weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI: 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+HER2- breast cancer.

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