Citations 1
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
Chien, A. Jo , Tripathy, Debasish , Albain, Kathy S. , Symmans, W. Fraser , Melisko, Michelle , Schwab, Richard B. , Forero‐Torres, Andres , Stringer-Reasor, Erica , Ellis, Erin D. , Nanda, Rita , Jaskowiak, Nora , Godellas, Constantine , Haley, Barbara , Kemmer, Kathleen, Clark, Amy S. , Lang, Julie E. , Lu, Janice , Korde, Larissa A. , Edmiston, Kirsten K., Northfelt, Donald W. , Viscusi, Rebecca K., Yee, Douglas , Perlmutter, Jane , Veer, Laura J. van’t , Wilson, Amy , Peterson, Garry , Buxton, Meredith , Paoloni, Melissa, Clennell, Julia L. , Matthews, Jeffrey B. , Steeg, Katherine, Singhrao, Ruby , Hirst, Gillian L. , Sanil, Ashish, Asare, Smita , Berry, Donald A. , Esserman, Laura J. , Symmans, W Fraser , Esserman, Laura J , Hirst, Gillian L , Yee, Douglas , Rugo, Hope S. , Wallace, Anne M. , Helsten, Teresa L. , Kaplan, Henry G. , Murthy, Rashmi Krishna , Boughey, Judy C. , Elias, Anthony , Isaacs, Claudine , Hylton, Nola M. , DeMichele, Angela , Berry, Scott , Matthews, Jeffrey B., Yau, Christina
Journal of Clinical Oncology | February 7, 2020 | Volume: 38 | Issue: 10 | Pages: 1059-1069
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.