I-SPY 2: First Results Based on Biomarkers/Genetic Signatures in Breast Cancer

Phoebe Starr

February 2014, Vol 5, No 1 - Personalized Medicine

San Antonio, TX—Veliparib plus carboplatin was identified as a worthy combination to move forward in trials of patients with triple-negative breast cancer (TNBC; ie, estrogen receptor–negative, progesterone receptor–negative, HER2-negative), a subtype of breast cancer with a very poor prognosis.

This combination was a “winner” in the phase 2 Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) 2 trial, a series of studies of novel agents and combinations of therapies in biomarker-identified subsets of patients. The trial has a unique adaptive design that allows screening of a series of novel agents in combination with standard neoadjuvant therapy for high-risk patients with breast cancer in small numbers of patients with a particular biomarker or signature.

These first efficacy results of I-SPY 2 showing that veliparib plus carboplatin “graduated” in TNBC were presented by Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California, San Francisco, at the 2013 San Antonio Breast Cancer Symposium. I-SPY 2 has also identified neratinib as a “graduate,” but those data are not yet available.

“Our goal is to accelerate the process of identifying drugs that are effective for specific breast cancer subtypes, and reduce the cost, time, and numbers of patients needed to get effective drugs to market. Today’s report is on 1 of 7 current experimental arms of I-SPY 2,” Dr Rugo told listeners at the meeting.

The study pits 12 weekly cycles of standard paclitaxel against 12 cycles of weekly paclitaxel plus novel agent A versus 12 weekly cycles of paclitaxel plus novel agent B. This treatment is followed by doxorubicin-based chemotherapy. Response is determined by pathologic complete response (pCR), defined as no residual invasive cancers in the breast and lymph nodes, and by magnetic resonance imaging (MRI) assessment after definitive surgery.

“Adaptive randomization based on the performance of regimens within biomarker subtypes/MammaPrint genetic signatures is the key for enrolling patients. Random probabilities are updated as the study proceeds according to MammaPrint signature, and the threshold for success is based on response for each patient’s tumor based on MRI and pCR assessment over time,” Dr Rugo explained.

The response of each patient informs the randomization assignment for the next patient on study, she continued. Each new patient benefits from the information obtained from the previous patient with that same signature. “This allows us to drop an agent that isn’t working,” Dr Rugo explained.

Randomization is assigned based on the performance of the experimental regimens within 8 biomarker subtypes (based on hormone receptor, HER2, and MammaPrint He-1 and Hi-2).

The results reported at the meeting included 71 evaluable patients, 44 of whom had TNBC. The estimated probabilities of pCR showed that the probability of success with veliparib plus carboplatin is 99%, mainly as a result of the success of this regimen in patients with TNBC. By contrast, veliparib plus carboplatin had little probability of succeeding in the HER2-positive/hormone receptor–positive subset of patients.

The ultimate plan for drugs that “graduate” in I-SPY 2 is a 300-patient phase 3 trial that includes the subset of patients who will benefit from that drug. “The phase 3 trial will incorporate outcome data to correspond with pCR. We hope this will be a mechanism for accelerated approval,” Dr Rugo said.