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. Journal Article


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
Article Title: 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.
Journal Title: Journal of Clinical Oncology
ISSN: 0732-183X
Publisher: Unknown  
Date Published: 2019