Initial results from a recent triple negative breast cancer clinical research trial (I-SPY 2) show encouraging possibilities for veliparib (developed by AbbVie Inc.) and neratinib (developed by Puma Biotechnology), as reported by Oncoloy Live.
Launched by the Foundation for the National Institutes of Health’s (FNIH) Biomarkers Consortium, the study employs a groundbreaking approach that, according to what leading researchers presented during the 2013 San Antonio Breast Cancer Symposium, may accelerate and influence the way that oncology drugs are tested and approved in the near future.
The I-SPY 2 trial uses an adaptive drug design approach in order to match experimental therapies with patients by looking at their specific genetic or biological markers. Gathering personalized information from individual triple negative breast cancer patients’ tumors allows researchers to offer a customized combination of treatments that better match the specific needs of each patient.
Investigators labeled the drugs used in patients as “graduates,” which are then eligible to move into phase III testing, explains 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.
Rugo presented data on the oral PARP inhibitor veliparib in combination with carboplatin. 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. AbbVie launched in January a phase III trial in which 620 patients with early-stage, triple-negative breast cancer will be randomized to one of three arms: veliparib in combination with carboplatin and paclitaxel; placebo plus carboplatin/paclitaxel; or placebo plus paclitaxel (NCT02032277). Patients in all arms would follow these regimens with doxorubicin/ cyclophosphamide.
Puma Biotechnology reported that Neratinib, an irreversible tyrosine kinase inhibitor that blocks epidermal growth factor signaling, graduated after showing a probability of superiority as part of a combination regimen with paclitaxel followed by doxorubicin/cyclophosphamide in patients who are HER2-positive and hormone receptor-negative. Full results would be presented at a future scientific meeting, the company said.
In the trial, experimental regimens can “graduate” in at least one of 10 possible signatures defined by hormone receptor, HER2 status, and MammaPrint. Rugo, who presented the results, said the trial’s 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.”
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 that “I-SPY 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 equal or larger than 2.5 cm by clinical exam and equal or larger than 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 only 300 patients with this disease subtype.
In other “signatures,” the combination was predicted to be far less successful, according to Rugo. In the HR-positive/HER2-negative group, for example, 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 triple-negative signature, the subset recommended for this regimen’s Hope S. Rugo, MD subsequent development.”