Novel Agents on Horizon for Triple-Negative Breast Cancer

Cynthia Ma, MD, PhD

There is a lack of targeted agents for triple-negative breast cancer (TNBC), which makes it one of the most challenging subtypes of breast cancer to treat; however, that may soon be changing, according Cynthia Ma, MD, PhD, at the 2016 International Congress on the Future of Breast Cancer.

“There is a lot of interest in immunotherapy and the checkpoint blockade agents,” said Ma, associate professor, medicine, Medical Oncology, Washington University School of Medicine in St. Louis. “There are also antibody-drug conjugates that are being developed as well, and there are several agents in that class.”

One of the most promising novel agents in development for TNBC is the gpNMB-targeted antibody-drug conjugate glembatumumab vedotin (CDX-011), which is being explored in the ongoing phase II METRIC trial, said Ma, who serves as the Washington University Principal Investigator for the trial.

“This antigen is present in about 40% of the TNBC cases,” said Ma. “The study selects those patients that are positive for this antigen to be eligible for this trial. Earlier phase trials have shown that TNBC patients, particularly when they have increased gpNMB expression, may have longer progression-free survival.”

In a prior phase II study of patients with breast cancer, those with gpNMB-expressing TNBC (n = 16) treated with glembatumumab vedotin had an objective response rate (ORR) of 33% compared with 0% in those treated with investigator's choice of therapy. When considering those with stable disease, the disease control rate with glembatumumab vedotin was 75% compared with 25% for those treated with chemotherapy.

Median progression-free survival (PFS) with the glembatumumab vedotin was 3.5 versus 1.5 months with investigator’s choice of therapy (HR, 0.11). Additionally, treatment with the antibody-drug conjugate nearly doubled overall survival (OS) compared with chemotherapy (median 10.0 vs 5.5 months; HR, 0.14).

The METRIC trial was based upon the success of this subgroup, and is randomizing 300 patients in a 2:1 ratio to receive glembatumumab vedotin or capecitabine. Patients are required to have gpNMB-positive advanced, locally advanced, recurrent, or metastatic settings TNBC. The primary endpoint of the trial is PFS and the final data analysis will occur after 203 PFS events. The estimated primary completion date is November 2016 (NCT01997333).

“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 TNBC are mutated in p53, which is not directly targetable,” said Ma. “gpNMB is a surface protein that is overexpressed and this antibody-drug conjugate really takes advantage, regardless of what kind of mutation the tumor may have. It will probably be applicable for a broader range of TNBC cases.”

The immune checkpoint inhibitors are also under exploration in TNBC; however, at this point, a distinct and effective biomarker has not yet emerged for this class of agents. “This is still an area of investigation,” said Ma. “The data has been controversial and also the assay for PD-L1 expression is not uniformly done yet, so it still needs to further develop.”

As a single-agent, pembrolizumab showed promise in the KEYNOTE-012 trial for patients with TNBC whose tumor samples were screened for PD-L1 expression.²Of 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 ORR was 18.5%, and the median time to response was 17.9 weeks (range, 7.3 to 32.4 weeks). The median duration of response was not yet reached (range, 15.0 to ≥ 47.3 weeks).

The median PFS with pembrolizumab was 1.9 months and the 6-month PFS rate was 24.4%. The median OS with the PD-1 inhibitor was 11.2 months and the 6- and 12-month OS rates were 66.7% and 43.1%, respectively.

“TNBC has a high mutational load. This is particularly true if you compare it with ER-positive patients,” said Ma. “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.”

A number of studies continue to assess various immunotherapies for patients with TNBC both as single-agents and in combinations. Ma is involved in a study looking at pembrolizumab with eribulin (Halaven), and other studies have assessed nab-paclitaxel (Abraxane) with atezolizumab (Tecentriq).

References

1. Yardley DA, Weaver R, Melisko ME, et al. EMERGE: A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB—expressing breast cancer.J Clin Oncol. 2015;33(14):1609-1619.
2. Nanda R, Laura QM, Chow E, et al. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study [Published online May 2, 2016]J Clin Oncol. 2016;doi: 10.1200/JCO.2015.64.8931.

“There are PD-L1 antibodies in development, many which are being investigated in combination with chemotherapy in this space,” said Ma. “We are participating in a phase I/II of pembrolizumab in combination with eribulin and that is ongoing. I know that there are also combination therapy trials of pembrolizumab with other immunotherapy agents in TNBC as well.”