A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III <i>PIK3CA</i>-Mutant ER-Positive and HER2-Negative Breast Cancer.

Abstract

<b>Purpose:</b> Hyperactivation 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 <i>PIK3CA</i>-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 <i>PIK3CA</i> mutant ER⁺ breast cancer.<b>Experimental Design:</b> Potential eligible patients with clinical stage II/III ER⁺/HER2^- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor <i>PIK3CA</i> sequencing. Patients positive for <i>PIK3CA</i> mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.<b>Results:</b> Fifty-one patients preregistered and 16 of 22 with <i>PIK3CA</i>-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (<i>n</i> = 2) and toxicity (<i>n</i> = 1). Thirteen 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 after MK-2206 persisted. One patient acquired an <i>ESR1</i> mutation at surgery.<b>Conclusions:</b> MK-2206 is unlikely to add to the efficacy of anastrozole alone in <i>PIK3CA</i>-mutant ER⁺ breast cancer and should not be studied further in the target patient population. <i>Clin Cancer Res; 23(22); 6823-32. ©2017 AACR</i>.