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.
- Author
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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
- Subjects
Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Prevention ,Breast Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Doxorubicin ,Female ,Heterocyclic Compounds ,3-Ring ,Humans ,Middle Aged ,Neoadjuvant Therapy ,Paclitaxel ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-akt ,Receptor ,ErbB-2 ,Receptors ,Steroid ,Trastuzumab ,I-SPY 2 Consortium ,Receptor ,erbB-2 ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
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.
- Published
- 2020