TY - JOUR
T1 - 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
AU - Chien, A. Jo
AU - Tripathy, Debasish
AU - Albain, Kathy S.
AU - Symmans, W. Fraser
AU - Rugo, Hope S.
AU - Melisko, Michelle E.
AU - Wallace, Anne M.
AU - Schwab, Richard
AU - Helsten, Teresa
AU - Forero-Torres, Andres
AU - Stringer-Reasor, Erica
AU - Ellis, Erin D.
AU - Kaplan, Henry G.
AU - Nanda, Rita
AU - Jaskowiak, Nora
AU - Murthy, Rashmi
AU - Godellas, Constantine
AU - Boughey, Judy C.
AU - Elias, Anthony D.
AU - Haley, Barbara B.
AU - Kemmer, Kathleen
AU - Isaacs, Claudine
AU - Clark, Amy S.
AU - Lang, Julie E.
AU - Lu, Janice
AU - Korde, Larissa
AU - Edmiston, Kirsten K.
AU - Northfelt, Donald W.
AU - Viscusi, Rebecca K.
AU - Yee, Douglas
AU - Perlmutter, Jane
AU - Hylton, Nola M.
AU - van’t Veer, Laura J.
AU - DeMichele, Angela
AU - Wilson, Amy
AU - Peterson, Garry
AU - Buxton, Meredith B.
AU - Paoloni, Melissa
AU - Clennell, Julia
AU - Berry, Scott
AU - Matthews, Jeffrey B.
AU - Steeg, Katherine
AU - Singhrao, Ruby
AU - Hirst, Gillian L.
AU - Sanil, Ashish
AU - Yau, Christina
AU - Asare, Smita M.
AU - Berry, Donald A.
AU - Esserman, Laura J.
N1 - Funding Information:
Supported by Quantum Leap Healthcare Collaborative, a 501(c)3 nonprofit (2013-present); the Foundation for the National Institutes of Health (2010-2012); and National Cancer Institute Center for Biomedical Informatics and Information Technology Grant No. 28XS197. Ongoing support for the I-SPY 2 Trial is from the Safeway Foundation, the William K. Bowes Jr Foundation, and Give Breast Cancer the Boot, and initial support was from Quintiles Transnational Corporation, the San Francisco Foundation, Side Out Foundation, Harlan Family, the Avon Foundation for Women, Alexandria Real Estate Equities, and private individuals and family foundations.
Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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 3 2 3 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.
AB - 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 3 2 3 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.
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U2 - 10.1200/JCO.19.01027
DO - 10.1200/JCO.19.01027
M3 - Article
C2 - 32031889
AN - SCOPUS:85082562138
SN - 0732-183X
VL - 38
SP - 1059
EP - 1069
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 10
ER -
