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Anticipated METRIC results could lead to first targeted agent approved in TNBC

Friday, November 11, 2016

Findings from a highly anticipated, randomized, phase II trial could possibly pave the path for the FDA approval of the first targeted therapy for patients with triple-negative breast cancer (TNBC), explains Linda T. Vahdat, MD, in this interview with Targeted Oncology.

The METRIC study is exploring the efficacy and safety of glembatumumab vedotin (CDX-011) versus standard capecitabine in this subset of patients, particularly in those with high levels of glycoprotein NMB (gpNMB) expression (NCT01997333). The antibody-drug conjugate is a novel approach designed to target a very difficult-to-treat patient population, whose sole approved treatment option is standard chemotherapy.

What is the current progress thus far with glembatumumab vedotin, and where are we going with it?  

Photo of Linda Vahdat, M.D.Linda Vahdat, M.D. Vahdat: Glembatumumab vedotin is an antibody-drug conjugate. The target on the antibody is called gpNMB, and it is important for invasion and migration. We have looked at glembatumumab vedotin in patients who have breast cancer. What we noticed is that it seemed to be most effective in patients who had high gpNMB expression on their tumors and who had triple-negative disease. That is why the registration trial—the METRIC trial—is looking to see how effective glembatumumab vedotin is in patients with TNBC with high gpNMB expression versus capecitabine, which is the standard treatment. The METRIC trial is a phase II trial of glembatumumab vedotin versus capecitabine and that trial is currently accruing.

What are the scientific questions to answer, as what are your goals for this trial?

Vahdat: TNBC is a very difficult-to-treat breast cancer and at least, so far, we don’t have anything that is more targeted than plain old chemotherapy for these patients. Therefore, there is a real unmet need for a targeted agent for these patients—for a strategy that improves outcomes. Patients with TNBC tend to do worse than the other types of breast cancer that we typically treat. 

What is glembatumumab vedotin’s mechanism of action and how does it compare with other antibody-drug conjugates? 

Vahdat: For patients with TNBC, the only really available agents right now—from a standard perspective—is chemotherapy. That is it. The only advance that has been made is administering chemotherapy to these patients. Therefore, glembatumumab works very differently. It’s an antibody-drug conjugate; the antibody part of it targets gpNMB, also known as osteoactivin. gpNMB is important for invasion and migration, so it helps the cells move around. This is linked to a chemotherapy drug known as monomethyl auristatin that is an antimicrotubule agent; it’s actually a pretty old drug. However, the problem is they couldn’t give it in vein to people because it was too toxic. When they are able to target it just to the tumor cell, the toxicity profile is actually quite acceptable. 

Anecdotally, how have you seen this drug tolerated in the patients who have enrolled thus far?  

Vahdat: It is typically a very well-tolerated drug. The biggest side effect is that patients can get a little bit of neutropenia, which is something we deal with all the time. A small proportion of patients may get a rash, because gpNMB is sometimes expressed on the skin. Another side effect is patients do lose their hair, which is the biggest problem. As we know, the patients—very reasonably—do not want to lose their hair. Generally speaking, it’s very well tolerated. 

What does the future hold for glembatumumab vedotin? Could we look at combining it with other agents?

Vahdat: It is hard to know what the future holds for glembatumumab vedotin. There is one thing we know if it turns out that it is more effective than standard therapy. When we see a patient’s TNBC, in addition to reconfirming the ER-, PR-, and HER2-negativity, we are going to be checking for gpNMB overexpression, so that is going to change in how we approach patients. 

After the METRIC trial, my hope is that we have an approval of the first targeted drug for TNBC.  

One of the things that are just really important when someone is diagnosed with metastatic breast cancer is that you have options. When you look at the natural history of the disease in people who do not have TNBC—say they are HER2-positive or HR-positive, called luminal breast cancers—they have lots of options. You have this big bucket that you pull of all of these options out of. When you have patients with TNBC, you only have one set of options—which is chemotherapy, so they’re really very limited. Having a drug such as glembatumumab vedotin would expand the options.

Additional coverage:

Targeted Therapy May Be the Future for Triple-Negative Breast Cancer, Expert Says - CURE Magazine

METRIC Trial Has Potential to Reform TNBC Landscape - Targeted Oncology