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

Abstract

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. Methods 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. Conclusion 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.

Is There a Future for AKT Inhibitors in the Treatment of Cancer?

“…In this issue of Clinical Cancer Research , Ma and colleagues (1) report the results of a phase I trial of MK-2206, an allosteric pan-AKT inhibitor, in combination with endocrine therapy (anastrozole, fulvestrant or both) in post-menopausal patients with metastatic ER+/HER2− breast cancer. In laboratory experiments, the combination of MK-2206 with fulvestrant induced significant apoptosis in human breast cancer cells resistant to long term estrogen deprivation, an experimental intervention equivalent to treatment with aromatase inhibitors, particularly in those with either PIK3CA or PTEN mutations.…”

AKT/PKB Signaling: Navigating the Network

“…As single agent therapy, however, MK2206 has not shown significant efficacy in the clinic (Ma et al, 2016). Unlike catalytic inhibitors, allosteric inhibitors target the closed, inactive conformation of AKT where the PH domain engages the kinase domain, thereby preventing phosphorylation and activation (Barnett et al, 2005; Hirai et al, 2010).…”

Clinical Implementation of Novel Targeted Therapeutics in Advanced Breast Cancer

“…A follow-up phase I trial of MK-2206 in combination with either anastrozole or fulvestrant or both, in a heterogenous population of patients with metastatic ERþ HER2 negative breast cancer resulted in 42% clinical benefit without disease progression for at least 6 months. Due to these promising results, a neoadjuvant Phase II trial is now underway [Ma et al, 2016b]. mTOR is found in two protein complexes, TORC1 and TORC2, which typically lie downstream and upstream of AKT, respectively.…”