A Phase II trial of neoadjuvant MK2206, an AKT inhibitor, with anastrozole in clinical stage 2 or 3 PIK3CA mutant ER positive and HER2 negative breast cancer

Purpose: Hyper-activation of AKT is common and associated with endocrine resistance in estrogen receptor positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were pre-registered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150mg PO weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of 4 28-days cycles of combination therapy before surgery. Serial biopsies were collected at pre-registration, C1D1 and C1D17. Results: Fifty-one patients pre-registered and 16 of 22 with PIK3CA mutant tumors received study drug. Three patients went off study due to C1D17 Ki67>10% (n=2) and toxicity (n=1). 13 patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 post MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA mutant ER+ breast cancer and should not be studied further in the target patient population.

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