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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.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2020 Apr 01; Vol. 38 (10), pp. 1059-1069. Date of Electronic Publication: 2019 Feb 07. - Publication Year :
- 2020
-
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.<br />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.<br />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).<br />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.
- Subjects :
- Adult
Aged
Antineoplastic Combined Chemotherapy Protocols adverse effects
Breast Neoplasms enzymology
Breast Neoplasms surgery
Doxorubicin administration & dosage
Doxorubicin adverse effects
Female
Heterocyclic Compounds, 3-Ring administration & dosage
Humans
Middle Aged
Neoadjuvant Therapy
Paclitaxel administration & dosage
Paclitaxel adverse effects
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors adverse effects
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Proto-Oncogene Proteins c-akt metabolism
Receptors, Steroid metabolism
Trastuzumab administration & dosage
Trastuzumab adverse effects
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Receptor, ErbB-2 biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1527-7755
- Volume :
- 38
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 32031889
- Full Text :
- https://doi.org/10.1200/JCO.19.01027