MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial

Abstract

Purpose: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.

Patients and methods: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.

Results: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).

Conclusion: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Trial registration: ClinicalTrials.gov NCT01042379.

FIG 1.

CONSORT diagram for primary efficacy analysis of MK-2206. HER2−, human epidermal growth factor receptor 2 negative; HER2+, human epidermal growth factor receptor 2 positive.

FIG 2.

Probability distributions for MK-2206 and control arms within each of the predefined biomarker signatures. The corresponding 95% probability intervals (PIs) are represented by the arrows for each. The mean of each distribution is the estimated rate of pathologic complete response (pCR). HER2−, human epidermal growth factor receptor 2 negative; HER2+, human epidermal growth factor receptor 2 positive; HR–, hormone receptor negative; HR+, hormone receptor positive; MP2, MammaPrint positive; Prob(>Ctl), probability superior to control; Prob(Ph3), probability of phase III success.

FIG 3.

Kaplan-Meier plots of event-free survival (EFS) in MK-2206 (blue) and control (red) arms for (A) all participants; (B) participants with hormone receptor-negative (HR−) breast cancer; (C) human epidermal growth factor receptor 2–positive (HER2+) breast cancer; and (D) HER2+/HR– breast cancer. Hazard ratios and 95% CIs are provided; however, caution is warranted in interpreting the results because of the low number of patients in each subtype and the fact that I-SPY 2 is not powered for survival end points. Ref, reference.