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
Authors: Chien A. Jo , Tripathy Debasish , Albain Kathy S. , Symmans W. Fraser , Rugo Hope S. , Melisko Michelle E. , Wallace Anne M. , Schwab Richard , Helsten Teresa , Forero-Torres Andres , Stringer-Reasor Erica , Ellis Erin D. , Kaplan Henry G. , Nanda Rita , Jaskowiak Nora , Murthy Rashmi , Godellas Constantine , Boughey Judy C. , Elias Anthony D. , Haley Barbara B. , Kemmer Kathleen , Isaacs Claudine , Clark Amy S. , Lang Julie E. , Lu Janice , Korde Larissa , Edmiston Kirsten K. , Northfelt Donald W. , Viscusi Rebecca K. , Yee Douglas , Perlmutter Jane , Hylton Nola M. , van’t Veer Laura J. , DeMichele Angela , Wilson Amy , Peterson Garry , Buxton Meredith B. , Paoloni Melissa , Clennell Julia , Berry Scott , Matthews Jeffrey B. , Steeg Katherine , Singhrao Ruby , Hirst Gillian L. , Sanil Ashish , Yau Christina , Asare Smita M. , Berry Donald A. , Esserman Laura J. ,   on behalf of I-SPY 2 Consortium
Published: February 2020

PURPOSEThe 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 METHODSI-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.RESULTSMK-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).CONCLUSIONThe 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.