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

作者：Ma Cynthia X^*; Suman Vera; Goetz Matthew P; Northfelt Donald; Burkard Mark E; Ademuyiwa Foluso; Naughton Michael; Margenthaler Julie; Aft Rebecca; Gray Richard; Tevaarwerk Amye; Wilke Lee; Haddad Tufia; Moynihan Timothy; Loprinzi Charles; Hieken Tina; Barnell Erica K; Skidmore Zachary L; Feng Yan Yang; Krysiak Kilannin; Hoog Jeremy; Guo Zhanfang; Nehring Leslie; Wisinski Kari B; Mardis Elaine; Hagemann Ian S; Vij Kiran; Sanati Souzan; Al Kateb Hussam

来源：Clinical Cancer Research, 2017, 23(22): 6823-6832.

DOI：10.1158/1078-0432.CCR-17-1260

Purpose: 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 PIK3CA-mutant ER+ breast cancer under estrogendeprived 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 preregistered 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 (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.
Results: Fifty-one patients preregistered 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). 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 ESR1 mutation at surgery.
Conclusions: MK-2206 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.

• 出版日期2017-11-15