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

被引：87

作者：

Chien, A. Jo ^{[1
]}

Tripathy, Debasish ^{[2
]}

Albain, Kathy S. ^{[3
]}

Symmans, W. Fraser ^{[2
]}

Rugo, Hope S. ^{[1
]}

Melisko, Michelle E. ^{[1
]}

Wallace, Anne M. ^{[4
]}

Schwab, Richard ^{[4
]}

Helsten, Teresa ^{[4
]}

Forero-Torres, Andres ^{[5
]}

Stringer-Reasor, Erica ^{[5
]}

Ellis, Erin D. ^{[6
]}

Kaplan, Henry G. ^{[6
]}

Nanda, Rita ^{[7
]}

Jaskowiak, Nora ^{[7
]}

Murthy, Rashmi ^{[2
]}

Godellas, Constantine ^{[3
]}

Boughey, Judy C. ^{[8
]}

Elias, Anthony D. ^{[9
]}

Haley, Barbara B. ^{[10
]}

Kemmer, Kathleen ^{[11
]}

Isaacs, Claudine ^{[12
]}

Clark, Amy S. ^{[13
]}

Lang, Julie E. ^{[14
]}

Lu, Janice ^{[14
]}

Korde, Larissa ^{[15
]}

Edmiston, Kirsten K. ^{[16
]}

Northfelt, Donald W. ^{[17
]}

Viscusi, Rebecca K. ^{[13
,18
]}

Yee, Douglas ^{[19
]}

Perlmutter, Jane ^{[20
]}

Hylton, Nola M. ^{[1
]}

van't Veer, Laura J. ^{[1
]}

DeMichele, Angela

Wilson, Amy ^{[21
]}

Peterson, Garry ^{[1
]}

Buxton, Meredith B. ^{[22
]}

Paoloni, Melissa ^{[22
]}

Clennell, Julia ^{[22
]}

Berry, Scott ^{[22
]}

Matthews, Jeffrey B. ^{[1
]}

Steeg, Katherine ^{[1
]}

Singhrao, Ruby ^{[1
]}

Hirst, Gillian L. ^{[1
]}

Sanil, Ashish ^{[22
]}

Yau, Christina ^{[1
]}

Asare, Smita M. ^{[21
]}

Berry, Donald A. ^{[22
]}

Esserman, Laura J. ^{[1
]}

机构：

[1] Univ Calif San Francisco, 1600 Divisadero St, San Francisco, CA 94115 USA

[2] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[3] Loyola Univ, Chicago, IL 60611 USA

[4] Univ Calif San Diego, La Jolla, CA 92093 USA

[5] Univ Alabama Birmingham, Birmingham, AL USA

[6] Swedish Canc Inst, Seattle, WA USA

[7] Univ Chicago, Med Ctr, Chicago, IL 60637 USA

[8] Mayo Clin, Rochester, MN USA

[9] Univ Colorado, Denver, CO 80202 USA

[10] Univ Texas Southwestern, Dallas, TX USA

[11] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[12] Georgetown Univ, Washington, DC USA

[13] Univ Penn, Philadelphia, PA 19104 USA

[14] Univ Southern Calif, Los Angeles, CA 90007 USA

[15] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA

[16] Inova Hlth Syst, Falls Church, VA USA

[17] Mayo Clin, Scottsdale, AZ USA

[18] Univ Arizona, Tucson, AZ USA

[19] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA

[20] Gemini Grp, Bad Axe, MI USA

[21] Quantum Leap Healthcare Collaborat, San Francisco, CA USA

[22] Berry Consultants, Austin, TX USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2020年 / 38卷 / 10期

基金：

美国国家卫生研究院;

关键词：

PATHOLOGICAL COMPLETE RESPONSE; AKT-INHIBITOR MK-2206; DOUBLE-BLIND; ADAPTIVE RANDOMIZATION; PIK3CA MUTATIONS; PLUS PACLITAXEL; TRASTUZUMAB; EVEROLIMUS; MULTICENTER; COMBINATION;

D O I：

10.1200/JCO.19.01027

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSEThe 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 METHODSI-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 x 2 x 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.RESULTSMK-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).CONCLUSIONThe 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. (c) 2020 by American Society of Clinical Oncology

引用

页码：1059 / +

页数：13

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