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 - 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 -