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.
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| Abstract | 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.
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| Authors | A Jo Chien, Debasish Tripathy, Kathy S Albain, W Fraser Symmans, Hope S Rugo, Michelle E Melisko, Anne M Wallace, Richard Schwab, Teresa Helsten, Andres Forero-Torres, Erica Stringer-Reasor, Erin D Ellis, Henry G Kaplan, Rita Nanda, Nora Jaskowiak, Rashmi Murthy, Constantine Godellas, Judy C Boughey, Anthony D Elias, Barbara B Haley, Kathleen Kemmer, Claudine Isaacs, Amy S Clark, Julie E Lang, Janice Lu, Larissa Korde, Kirsten K Edmiston, Donald W Northfelt, Rebecca K Viscusi, Douglas Yee, Jane Perlmutter, Nola M Hylton, Laura J Van't Veer, Angela DeMichele, Amy Wilson, Garry Peterson, Meredith B Buxton, Melissa Paoloni, Julia Clennell, Scott Berry, Jeffrey B Matthews, Katherine Steeg, Ruby Singhrao, Gillian L Hirst, Ashish Sanil, Christina Yau, Smita M Asare, Donald A Berry, Laura J Esserman, I-SPY 2 Consortium |
| Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 38 Issue 10 Pg. 1059-1069 (04 01 2020) ISSN: 1527-7755 [Electronic] United States |
| PMID | 32031889 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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