Back to Search Start Over

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.

Authors :
Chien AJ
Tripathy D
Albain KS
Symmans WF
Rugo HS
Melisko ME
Wallace AM
Schwab R
Helsten T
Forero-Torres A
Stringer-Reasor E
Ellis ED
Kaplan HG
Nanda R
Jaskowiak N
Murthy R
Godellas C
Boughey JC
Elias AD
Haley BB
Kemmer K
Isaacs C
Clark AS
Lang JE
Lu J
Korde L
Edmiston KK
Northfelt DW
Viscusi RK
Yee D
Perlmutter J
Hylton NM
Van't Veer LJ
DeMichele A
Wilson A
Peterson G
Buxton MB
Paoloni M
Clennell J
Berry S
Matthews JB
Steeg K
Singhrao R
Hirst GL
Sanil A
Yau C
Asare SM
Berry DA
Esserman LJ
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.

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