A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or IIIPIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer

Abstract

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 -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 mutant ER breast cancer. 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 sequencing. Patients positive for 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. Fifty-one patients preregistered and 16 of 22 with -mutant tumors received study drug. Three patients went off study due to C1D17 Ki67>10% ( = 2) and toxicity ( = 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 mutation at surgery. MK-2206 is unlikely to add to the efficacy of anastrozole alone in -mutant ER breast cancer and should not be studied further in the target patient population. .

ESR1 mutations in breast cancer

“…62 There were no pathological complete responses (pCR) in the ERpositive population, and there was no additional suppression of tumor cell proliferation with the addition of MK-2206. A single-arm, phase 2 neoadjuvant clinical trial was conducted using the AKT inhibitor MK-2206 in combination with anastrozole in advanced breast cancer patients with a PIK3CA mutation.…”

“…A single-arm, phase 2 neoadjuvant clinical trial was conducted using the AKT inhibitor MK-2206 in combination with anastrozole in advanced breast cancer patients with a PIK3CA mutation. 62 There were no pathological complete responses (pCR) in the ERpositive population, and there was no additional suppression of tumor cell proliferation with the addition of MK-2206. 62 Furthermore, a patient in this study acquired an ESR1 mutation detected at the time of surgery.…”

“…62 There were no pathological complete responses (pCR) in the ERpositive population, and there was no additional suppression of tumor cell proliferation with the addition of MK-2206. 62 Furthermore, a patient in this study acquired an ESR1 mutation detected at the time of surgery. Although not statistically powered for analysis, this observation could suggest clinical resistance of ESR1 mutations to AKT inhibitors.…”

Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

“…These findings, together with the upcoming results of the SANDPIPER phase III study (fulvestrant ± taselisib, NCT02340221) in the metastatic setting will help to define the further development of taselisib. Another reported trial in the NA context is the phase II single-arm trial with MK-2206, a pan-AKT inhibitor [36]. Potential eligible patients with clinical stage II/III were preregistered and received anastrozole (plus goserelin if premenopausal) for 28 days in cycle 0, pending tumor PIK3CA analysis.…”

Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

“…These studies identified HER2 mutation and phosphorylation as mechanisms by which ER + HER2 non-amplified (henceforth referred to as ER + HER2 -) breast cancer cells could resist endocrine treatment 2,11 . However, translation of these findings proved challenging with results from clinical trials not living up to preclinical promise 3,6 . There is recognition now that this is likely because only a subset of ER + breast cancers activate HER2 to resist endocrine therapy.…”