Dataset Information

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.

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.

SUBMITTER: Chien AJ

PROVIDER: S-EPMC7106976 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

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.

Chien A Jo AJ Tripathy Debasish D Albain Kathy S KS Symmans W Fraser WF Rugo Hope S HS Melisko Michelle E ME Wallace Anne M AM Schwab Richard R Helsten Teresa T Forero-Torres Andres A Stringer-Reasor Erica E Ellis Erin D ED Kaplan Henry G HG Nanda Rita R Jaskowiak Nora N Murthy Rashmi R Godellas Constantine C Boughey Judy C JC Elias Anthony D AD Haley Barbara B BB Kemmer Kathleen K Isaacs Claudine C Clark Amy S AS Lang Julie E JE Lu Janice J Korde Larissa L Edmiston Kirsten K KK Northfelt Donald W DW Viscusi Rebecca K RK Yee Douglas D Perlmutter Jane J Hylton Nola M NM Van't Veer Laura J LJ DeMichele Angela A Wilson Amy A Peterson Garry G Buxton Meredith B MB Paoloni Melissa M Clennell Julia J Berry Scott S Matthews Jeffrey B JB Steeg Katherine K Singhrao Ruby R Hirst Gillian L GL Sanil Ashish A Yau Christina C Asare Smita M SM Berry Donald A DA Esserman Laura J LJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20190207 10

<h4>Purpose</h4>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.<h4>Patients and methods</h4>I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive ...[more]

PMID: 32031889

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Dataset Information

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.

Purpose

Patients and methods

Results

Conclusion

Publications

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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