Citations 1
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
Cynthia, X. , Northfelt, Donald W. , Margenthaler, Julie A. , Aft, Rebecca , Gray, Richard J. , Wilke, Lee G. , Haddad, Tufia C. , Moynihan, Timothy J. , Loprinzi, Charles L. , Barnell, Erica K. , Skidmore, Zachary L. , Feng, Yan-Yang, Krysiak, Kilannin , Guo, Zhanfang , Nehring, Leslie, Wisinski, Kari B. , Sanati, Souzan , Al‐Kateb, Hussam , Griffith, Obi L. , Griffith, Malachi , Doyle, L. Austin, Erlichman, Charles , Suman, Vera, Northfelt, Donald, Haddad, Tufia, Moynihan, Timothy, Loprinzi, Charles, Hieken, Tina, Krysiak, Kilannin , Griffith, Malachi , Griffith, Obi L , Suman, Vera J. , Goetz, Matthew P. , Burkard, Mark E. , Ademuyiwa, Foluso O. , Naughton, Michael J. , Tevaarwerk, Amyé , Hieken, Tina J. , Hoog, Jeremy , Mardis, Elaine R. , Hagemann, Ian S. , Vij, Kiran R , Ellis, Matthew J.
Clinical Cancer Research | September 5, 2017 | Volume: 23 | Issue: 22 | Pages: 6823-6832
Abstract 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 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 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. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.