Innovative I-SPY 2 Trial Yields First Results in Triple-Negative Breast Cancer

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Peter Ravdin, MD, PhD

Hope S. Rugo, MD

Donald A. Berry, PhD

Laura J. Esserman, MD, MBA

I-SPY 2 is a new way of getting new drugs into clinical testing more rapidly. This is very important as our number of novel treatment options expands.

—Peter Ravdin, MD, PhD

An innovative approach to streamlining the testing of novel agents in breast cancer has yielded some of its first results, which were reported at the 2013 San Antonio Breast Cancer Symposium.1

Adaptive Trial Design

The veliparib/carboplatin plus standard neoadjuvant therapy regimen is currently one of seven experimental treatments evaluated to date in the multidrug I-SPY 2 trial, which uses an adaptive design based on biomarker subtypes to evaluate novel agents in the neoadjuvant setting. The objective of the novel approach is to speed up and therefore revolutionalize the way that oncology drugs are tested and approved, said Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

The strategy involves the evaluation of drugs in small study populations, using advanced statistical techniques that promptly cull potential winners from losers. Experimental regimens can “graduate” in at least one of 10 possible signatures defined by hormone receptor status, HER2 status, and MammaPrint. This propels the drugs into phase III trials. Veliparib is the first drug to complete testing in the innovative study.

“Our goal is to identify and graduate regimens that have at least an 85% Bayesian predictive probability of success in [future] 300-patient biomarker-linked phase III neoadjuvant trials,” she said.

Peter Ravdin, MD, PhD, Breast Cancer Researcher and Biostatistician, San Antonio, Texas, and Co-Director of the symposium, and moderator of the press conference where the results were presented, commented, “I-SPY 2 is a new way of getting new drugs into clinical testing more rapidly. This is very important as our number of novel treatment options expands.”

Benefit From Veliparib/Carboplatin

In a study of 71 patients, veliparib/carboplatin, added to standard neoadjuvant chemotherapy, produced a pathologic complete response rate of 52%, and thus the novel agent “graduated” with the triple-negative signature, which is the subset recommended for this regimen’s subsequent development, said Dr. Rugo.

In other “signatures,” the combination was predicted to be far less successful. For example, for the hormone receptor–positive/HER2-negative group, the estimated pathologic complete response rate was 14% for the combination and 19% for controls, she said.

“The I-SPY 2 standing trial mechanism efficiently evaluates agents and combinations in biomarker-defined patient subsets,” Dr. Rugo said. “This adaptive trial successfully identified a biomarker signature/drug pair for veliparib/carboplatin on the basis of a modest number of patients.”

Simultaneous Testing of Many Drugs

I-SPY 2 is sponsored by the Biomarkers Consortium, which represents 20 sites across the United States and Canada, and the trial is the work of over 100 investigators and advocates. Laura J. Esserman, MD, MBA, Professor of Surgery and Radiology and Director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco, Comprehensive Cancer Center is the co–principal investigator for I-SPY 2, and the other co–principal investigator is Donald A. Berry, PhD, Professor in the Department of Biostatistics at The University of Texas MD Anderson Cancer Center, Houston.

Dr. Esserman emphasized the value of the study design. “The trial enables many drugs to be tested simultaneously, and it shows that many collaborators can work together and get faster results,” she told The ASCO Post. “The idea is to let the phase II trial be the screening trial, and to move forward the drugs with the biggest signals. We believe the right path forward is to do this as one trial. We want to make the process seamless.”

The phase III testing of veliparib will be powered for event-free survival. In addition to veliparib, Dr. Esserman noted, neratinib has also graduated from the I-SPY 2 trial, and findings for the neratinib-containing regimen will be presented at the upcoming Annual Meeting of the American Association for Cancer Research in April. ■

Disclosure: Drs. Essserman, Berry, Rugo, and Ravdin reported no potential conflicts of interest.


1. Rugo HS, Olopade O, DeMichele A, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 trial. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013.