ONCAlert | 2017 San Antonio Breast Cancer Symposium

METRIC Trial Has Potential to Reform TNBC Landscape

Gina Columbus
Published Online: 1:35 PM, Fri December 9, 2016

Denise A. Yardley, MD

While targeted agents have advanced the field of hormone receptor (HR)–positive and HER2-positive breast cancers, patients with triple-negative breast cancer (TNBC) continue to be limited to chemotherapy. 
 
However, an ongoing randomized study exploring the prospect of an antibody-drug conjugate could transform treatment for these patients.
 
The phase II METRIC trial is investigating the safety and efficacy of glembatumumab vedotin (CDX-011) compared with standard capecitabine in patients with TNBC, particularly in those with high levels of glycoprotein NMB (gpNMB) expression (NCT01997333). The international study continues to accrue patients.
 
“We have had great uptake, now bringing on France, Italy, Germany, the United Kingdom, and then we have Australia, Canada,” says lead investigator Denise A. Yardley, MD. “It really does reflect a worldwide change in breast cancer.”
 
In an interview with Targeted Oncology during the 2016 San Antonio Breast Cancer Symposium, Yardley, who is senior investigator of the Breast Cancer Research Program, and principal investigator at the Sarah Cannon Research Institute, shares the rationale for the METRIC trial, the uniqueness of glembatumumab vedotin, and how the antibody-drug conjugate has the power to transform the field of TNBC.
 
TARGETED ONCOLOGY: What is the rationale to conduct the ongoing METRIC trial?

Yardley: The METRIC trial is a very exciting trial in the triple-negative patient population that is looking at a novel compound—glembatumumab vedotin—which is an antibody-drug conjugate. The trial really arose out of the earlier EMERGE trial, which looked at an unselected metastatic breast cancer population. Glembatumumab was randomized against an investigator’s choice of chemotherapy agents. In that trial, we didn’t select patients but we did measure gpNMB, which is a cell surface protein that is important for invasion and metastases.

In that all-comer trial, we found that the signal of gpNMB expression was high in the TNBC population, at about 40%. If you selected the patients with TNBC who bore that cell surface receptor, those patients stood to obtain the best response from glembatumumab. The studies showed that there are response rates, though small numbers, which are surging to 40%.

TARGETED ONCOLOGY: What is the design of the METRIC trial?

Yardley: There is a lot of enthusiasm now over looking at a signal in a triple-negative population. The METRIC trial stemmed out of that earlier phase II trial. This is selective for patients whose tumors have gpNMB expression of greater than 25%, and have triple-negative disease. They had to have 0 to 2 prior chemotherapies in the metastatic setting and tissue from the metastatic setting, which has been a novelty added. We are now looking at that biomarker and using it to screen a select TNBC population for the METRIC trial. Patients are randomized in a 2:1 fashion against capecitabine, so it’s a standard agent for patients.

The trial has done well and it’s accruing well. We are expecting it to close in 2017. It is open in North America, Canada, Australia, and about 5 European sites. We are really enthusiastic about seeing the end of accrual being reached.
 
It was very well tolerated as a compound, so now we are really looking for that signal with the biomarker-selected TNBC. This is an area that hasn’t had an antibody-drug conjugate, a biomarker-based study, or a drug approved. We are hoping to see that move forward and hopefully have a positive result.

TARGETED ONCOLOGY: What do you find to be so remarkable about this agent?

Yardley: It is the whole antibody-drug conjugate as a category. There was so much enthusiasm when trastuzumab emtansine (T-DM1; Kadcyla) was approved; for breast cancer, that was a very welcome agent. Now, we are really exploring the delivery of drugs in a very precise manner—of looking for a cell surface receptor to be a target for a drug, and then have enhanced delivery very select to the cells that overbear that expression. We know how that works for T-DM1. It was a very well tolerated and active agent.
 
Now, we are seeing that carry out to other solid tumors with other compounds. Glembatumumab vedotin falls right in that category. It would be a very select agent and another antibody-drug conjugate added to that breast cancer area—specifically, for the TNBC population that just hasn’t had a specific targeted agent to date.

TARGETED ONCOLOGY: You mentioned that glembatumumab was found to be well tolerated in an earlier trial. What adverse events, if any, were reported?

Yardley: You get that spectrum of there being a chemotherapy backbone, so there is certainly some fatigue, neutropenia, and there can be some neuropathy—and rash. Rash is probably the newest, in terms of what is least like a standard chemotherapy agent that’s managed. Most of these are managed with dose modifications or reductions, and patients are able to move forward with the therapy.

TARGETED ONCOLOGY: Do you think there may be other biomarkers aside from gpNMB?

Yardley: That looks to be the sole biomarker. It’s quite interesting; there are a lot of data showing that it’s a poor prognostic factor. It is found on other tumors; it is not exclusive to TNBC. It has been looked at in melanoma and in lung cancer.
 
Across the board, the signal has been that those tumors that bear the gpNMB cell surface protein have a poor prognosis. Maybe targeting it with an agent—very much like HER2-directed therapy—may be able to change the outcome of that disease by a very drug-targeted agent.

TARGETED ONCOLOGY: Is it worth exploring glembatumumab vedotin in other breast cancer subtypes?

Yardley: Clearly, there was definitely a signal from the EMERGE trial. The signal certainly seems to be more prevalent when you screen for gpNMB. In the HR-positive cohort, the responses were there, but to a lesser degree. Therefore, the value seems to be much higher in the TNBC subgroup.
 
However, we are learning more about estrogen receptor signaling and, within those subtypes, maybe some luminal B subtypes. There is definitely a signal to explore further. From that data, TNBC popped right out with having high expression, being able to screen for it, and [experiencing] a good response if you expressed it.

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