I-SPY 2 Results Identify Subset of Breast Cancer Patients Most Likely to Benefit From Neratinib


Key Points

  • The I-SPY2 adaptive trial determined HER2-positive, hormone receptor–negative breast cancer to be a biomarker signature for the pan-HER inhibitor neratinib.
  • A Bayesian algorithm used in the trial predicted that the neratinib-containing regimen would be highly likely to succeed in a phase III trial of hormone receptor–negative, HER-positive breast cancer.
  • Neratinib is under consideration for phase III testing in I-SPY 3 in the HER2-positive/hormone receptor–negative signature or in all HER2-positive patients.

Findings from the I-SPY 2 randomized phase II clinical trial for women with newly diagnosed stage II breast cancer show that a neoadjuvant regimen containing the investigational drug neratinib, a pan-HER inhibitor, and standard chemotherapy is beneficial for patients with hormone receptor–negative, HER2-positive primary breast cancer. The study was presented today at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego.

Study Details

The clinical trial used adaptive randomization, a prespecified and automated algorithm that preferentially assigns a patient with a particular subtype of breast cancer to treatment regimens that are performing better in patients with the same type of breast cancer. The algorithm triggers the decision to “graduate” when 60 to 120 patients are enrolled. Eligible patients had stage II breast cancer with a tumor size of at least 2.5 cm and were considered to be at high risk for early breast cancer recurrence based on an evaluation by the MammaPrint diagnostic test.

The primary endpoint of this study was pathologic complete response in breast and lymph nodes at the time of surgery. The study goal was to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoaduvant 300-patient phase III trial defined by hormone receptor status, HER2 status, and MammaPrint.


The algorithm randomly assigned 115 patients to the neratinib arm of the trial. The rates of pathologic complete response in the neratinib arm were compared with those of 78 patients who were concurrently randomly assigned to the control arm containing standard chemotherapy. These comparisons were made for 10 biomarker signatures prospectively defined by categories of hormone receptor status, HER2 status, and MammaPrint.

The researchers concluded that the probability that the neratinib-containing regimen has a higher rate of pathologic complete response than control therapy in hormone receptor–negative, HER2-positive breast cancer was 95%. The regimen’s predictive probability of success in a future, randomized 300-patient phase III trial was determined to be 79%.

The algorithm also predicted the neratinib drug combination is likely to be beneficial for all HER2-positive breast cancer patients, with the probability of superiority over standard therapy and the probability of success in a phase III trial being 95% and 73%, respectively.

The I-SPY 2 clinical trial’s adaptive statistical design was developed by the overall principal investigators for the I-SPY trial, Laura J. Esserman, MD, MBA, of UCSF Helen Diller Family Comprehensive Cancer Center, and Donald A. Berry, PhD, of The University of Texas MD Anderson Cancer Center and Berry Consultants.

“Clinical trial designs have to change to keep pace with the amazing advances being made in biology. I-SPY 2 may not be the final answer, but so far it has been successful in expanding the boundaries of clinical trials, making them more patient-friendly while preserving their scientific integrity,” Dr. Esserman said in a statement. 

I-SPY 2 is sponsored by QuantumLeap Healthcare Collaborative.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.