I-SPY 2 Uses Biomarker Subsets to Evaluate Treatments

Hope S. Rugo, MD

The I-SPY 2 trial, which is evaluating novel agents in the neoadjuvant treatment of breast cancer, may accelerate and influence the way that oncology drugs are tested and approved in the near future. Some of the first results of this effort were reported at the 2013 San Antonio Breast Cancer Symposium.

The approach involves evaluating drugs in small study populations, using advanced statistical techniques that will promptly identify potentially successful cohorts. The investigators have labeled these selective cohorts the “graduates,” which will then be eligible to move into phase III testing, according to Hope S. Rugo, MD, who presented the data, including encouraging possibilities for a veliparib/carboplatin combination therapy in triple-negative breast cancer.

Rugo is 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 in San Francisco.

The innovative, multidrug, phase II I-SPY 2 trial uses an adaptive design, based on biomarker subtypes, to evaluate a series of novel agents and combinations added to standard neoadjuvant therapy. The aim is to determine which types of patients respond best to particular therapies. Experimental regimens can “graduate” in at least one of 10 possible signatures defined by hormone receptor, HER2 status, and MammaPrint.

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

The presentation focused on the oral PARP inhibitor veliparib in combination with carboplatin, one of seven experimental regimens evaluated to date. Veliparib/ carboplatin improved pathologic complete response (pCR) rates in women with triple-negative breast cancer, thus qualifying the drug to move to the next round of clinical trial testing.

Study Population Where Benefit Was Seen

Peter Ravdin, MD, PhD, clinical professor of Oncology in San Antonio, Texas, co-director of the symposium and moderator of the press conference where the results were presented, commented, “ISPY 2 is not only positive, but it’s a new way of getting new drugs into clinical testing more rapidly. This is very important as our number of novel treatment options expands.”Women with tumors ≥2.5 cm by clinical exam and ≥2.0 cm were eligible for screening, and those considered triple- negative (hormone receptor- [HR-] negative by low MammaPrint score and HER2-negative) were eligible for randomization to standard neoadjuvant chemotherapy—paclitaxel followed by anthracycline-based chemotherapy— or to paclitaxel plus a novel agent, followed by anthracycline-based chemotherapy before surgery.

The estimated pCR rate was 52% with veliparib/carboplatin versus 26% with chemotherapy alone, with a 95% probability that this regimen is superior to the control, Rugo reported. The investigators were able to determine the combination’s potential after testing only 71 women, and after only 6 months of treatment. They predicted a 90% probability of success in a future trial of 300 patients with this disease subtype.

In other “signatures,” the combination was predicted to be far less successful, according to Rugo. For example, in the HR-positive/HER2-negative group, the estimated pCR rate was 14% for the combination and 19% for controls.

“The I-SPY 2 standing trial mechanism efficiently evaluates agents and combinations in biomarker-defined patient subsets. This adaptive trial successfully identified a biomarker signature/ drug pair for veliparib plus carboplatin on the basis of a modest number of patients,” Rugo said. “Veliparib/carboplatin has graduated with the triplenegative signature, the subset recommended for this regimen’s subsequent development.”