A number of clinical trials are exploring novel treatments for patients with breast cancer across a variety of settings. Recently, the phase III BOLERO-3 trial examined the addition of everolimus to the combination of trastuzumab and vinorelbine in women with HER2-positive metastatic breast cancer. The median progression-free survival with the addition of everolimus was 7 months versus 5.78 months in the placebo group.

Overall, the addition of everolimus resulted in more toxicity with a minimal improvement in efficacy, states Hope S. Rugo, MD. The lack of greater efficacy leads Joyce A. O’Shaughnessy, MD, to question whether the estrogen receptor may have been upregulated by the combination of the HER2 and mTOR inhibitors. This theory calls for further investigation, she believes.

With a variety of new agents becoming available, a larger emphasis is being placed on rapid, adaptive clinical trial design. In the I-SPY 2 trial, multiple drugs are being explored across several cohorts that are based on 10 signatures, such as hormone receptor (HR) status, HER2 status, and MammaPrint risk assessments. Patients are assigned to cohorts and randomized to receive a novel agent with or without standard neoadjuvant chemotherapy. Moreover, Rugo notes, the trial is designed to be flexible, allowing for changes as standards of care evolve.

Following surgery, pathologic complete response (pCR) rates are compared between the patients with each signature to identify a subpopulation most likely to respond. Once identified, larger phase III trials will be formed to confirm the findings.

The first results from the I-SPY 2 trial demonstrated encouraging possibilities for veliparib (ABT-888) in triple-negative breast cancer and neratinib (PB272) in patients who are HER2-positive and HR-negative. Furthermore, Rugo notes, based on the design of the trial, these agents have an 85% Bayesian predictive probability for success in future 300-patient phase III neoadjuvant trials with pCR as a primary endpoint.