Immunotherapy, Targeted Options Emerge in Triple-Negative Breast Cancer

Cynthia Ma, MD

There is a lack of targeted therapies or immunotherapy agents for triple-negative breast cancer (TNBC), making it a challenging subtypes of breast cancer to treat, Cynthia Ma, MD, PhD, said during a presentation at the 2016 International Congress on the Future of Breast Cancer.

However, there are several new treatment options on the horizon that have potential, added Ma, who is an associate professor of Medicine, Medical Oncology at the Washington University School of Medicine in St. Louis.

“There is a lot of interest in immunotherapy and the checkpoint blockade agents,” Ma noted. “There are also antibody-drug conjugates that are being developed, as well, and there are several agents in that class.”

The KEYNOTE-012 trial¹ investigated single-agent pembrolizumab (Keytruda) in patients with TNBC—as well as those with gastric, urothelial, and head and neck cancers—whose tumor samples were screened for PD-L1 expression. Of 111 patients, 58.6% had PD-L1—positive tumors and 32 were enrolled and assessed for safety and antitumor activity.

Among the 27 patients who were evaluable for antitumor activity, the overall response rate was 18.5%, the median time to response was 17.9 weeks (range, 7.3-32.4), and the median duration of response was not yet reached (range, 15.0 to ≥ 47.3).

The antibody-drug conjugate glembatumumab vedotin (CDX-011) is also being investigated in the ongoing, phase II METRIC trial for patients with TNBC and is an agent with promise, said Ma, who serves as the Washington University principal investigator for the METRIC trial.

The trial is investigating glembatumumab vedotin and capecitabine in 300 women who have glycoprotein NMB (gpNMB)-positive TNBC in the advanced, locally advanced, recurrent, or metastatic settings. The primary endpoint of the trial is progression-free survival (PFS) and final data analysis will occur after 203 PFS events.

OncLive: Can you discuss the ongoing phase II METRIC trial of glembatumumab vedotin?

What is the role of gpNMB and other actionable mutations in TNBC?

What other markers are showing potential? Could PD-L1 have utility?

Are there ongoing trials investigating immunotherapy in TNBC that you see potential for?

Why might immunotherapy have potential in TNBC compared with other breast cancer subtypes?

In an interview with OncLive, Ma provides insight on the potential of glembatumumab vedotin and immunotherapies on the horizon in the field of TNBC.Ma: The METRIC trial is a randomized study comparing CDX-011 versus capecitabine in patients with metastatic TNBC. Patients are randomized in a 2:1 ratio to CDX-011, an antibody-drug conjugate against gpNMB, or capecitabine. This antigen is present in about 40% of TNBC cases. The study selects those patients who are positive for this antigen to be eligible for this trial. Earlier phase trials have shown that patients with TNBC, particularly when they have increased gpNMB expression, may have longer PFS.TNBC has been extensively studied and sequenced. The issue with TNBC is that most of the mutations occur in tumor suppressors. For example, about 80% of TNBCs are mutated in p53, which is not directly targetable. gpNMB, however, is a surface protein that is overexpressed. This antibody-drug conjugate really takes advantage, regardless of what mutation the tumor may have. It will probably be applicable for a broader range of TNBC cases.This is still an area of investigation. The data have been controversial and also the assay for PD-L1 expression is not uniformly done yet, so it still needs to further develop.Yes. We are participating in a phase I/II study of pembrolizumab (Keytruda) in combination with eribulin (Halaven) and that is ongoing. There are also combination therapy trials of pembrolizumab with other immunotherapy agents in TNBC, as well. In addition to pembrolizumab, there are PD-L1 antibodies in development, many of which are being investigated in combination with chemotherapy in this space.TNBC has a high mutational load. This is particularly true if you compare it with ER-positive patients. In neoadjuvant studies, immune-cell infiltrates have been shown to correlate with responses and long-term outcomes, so there is some evidence that TNBC may be more immunogenic. That is one of the reasons that this class of agents may be more effective in TNBC.

1. Nanda R, Chow, LQM, Dees EC. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study [published online May 2, 2016]. J Clin Oncol. doi: 10.1200/JCO.2015.64.8931