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

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. HaleyKathleen 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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 3 2 3 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.

Original languageEnglish (US)
Pages (from-to)1059-1069
Number of pages11
JournalJournal of Clinical Oncology
Volume38
Issue number10
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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