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.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
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.
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; and Esserman, Laura J, "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." (2019). Articles, Abstracts, and Reports. 2881.