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Author Notes:

Address reprint requests to Dr. Esserman at the UCSF Carol Franc Buck Breast Care Center, University of California, San Francisco, 1600 Divisadero St., Box 1710, San Francisco, CA 94115, or at laura.esserman@ucsf.edu.

We thank Anna Barker for leadership in helping to launch the I-SPY 2 trial; the members of the data and safety monitoring committee (Harold Burstein, Elizabeth Frank, Steven Goodman, Clifford Hudis, Robert Mass, Musa Meyer, and Janet Wittes) for meeting monthly to review the safety data; the trial coordinators; Ken Buetow and the staff of caBIG for input with the informatics design; the entire project oversight committee; and our patient advocates, investigators, and all the patients who participated in the trial.

A complete list of the participating centers and investigators in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY 2 TRIAL) is provided in the Supplementary Appendix.

For author disclosures, please see the full article.


Research Funding:

Supported by QuantumLeap Healthcare Collaborative (from 2013 through the present) and the Foundation for the National Institutes of Health (from 2010 through 2012) and by a grant (28XS197) from the National Cancer Institute Center for Biomedical Informatics and Information Technology.

Initial support for the I-SPY 2 trial was provided by the Safeway Foundation, the Bill Bowes Foundation, Quintiles Transnational, Johnson & Johnson, Genentech, Amgen, the San Francisco Foundation, Give Breast Cancer the Boot, Eli Lilly, Pfizer, Eisai, the Side Out Foundation, the Harlan Family, the Avon Foundation for Women, Alexandria Real Estate Equities, and private persons and family foundations.


  • Science & Technology
  • Life Sciences & Biomedicine
  • General & Internal Medicine

Adaptive Randomization of Neratinib in Early Breast Cancer

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Journal Title:

New England Journal of Medicine


Volume 375, Number 1


, Pages 11-22

Type of Work:

Article | Final Publisher PDF


BACKGROUND: he heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature (“graduation”). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor–negative signature. Among patients with HER2-positive, hormone-receptor–negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor–negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.)

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© 2016 Massachusetts Medical Society.

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