Anticipated METRIC Results Could Lead to First Targeted Agent Approved in TNBC


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.<br /> &nbsp;

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, Vahdat stresses.

In an interview withTargeted Oncology, Vahdat, a professor of Medicine, Breast Cancer Research Program Leader at Meyer Cancer Center, at Weill Cornell Medicine and NewYork-Presbyterian, touches on the goals of the METRIC trial, how glembatumumab vedotin distinguishes itself from other agents, and how METRIC&rsquo;s results, if positive, could have a dramatic influence on the treatment paradigm of TNBC.

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

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&mdash;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.

TARGETED ONCOLOGY: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&rsquo;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.&nbsp;

TARGETED ONCOLOGY:What is the design of the METRIC trial?Vahdat:Patients are considered eligible for the METRIC trial if they have TNBC, which is defined as having estrogen receptor (ER) and progesterone receptor (PR) at less than 10% and being negative for HER2. They need to have gpNMB staining, which is the target of the antibody, and it needs to be positive on 25% of epithelial cells. Also, patients have to be minimally pretreated. They can have anywhere between 0 and 2 regimens, and they can't have had prior capecitabine. If they have had prior brain metastases, the metastases have to be inactive. Patients need to be in pretty good shape to be considered for the clinical trial.

The way it is structured is a 1:1 randomization between glembatumumab versus capecitabine. The primary endpoint of the clinical trial is progression-free survival; secondary endpoints are response rate, duration of response, overall survival, and toxicity.

TARGETED ONCOLOGY:What is glembatumumab vedotin&rsquo;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&mdash;is chemotherapy. That is it. The only advance that has been made is administering chemotherapy to these patients. Therefore, glembatumumab works very differently. It&rsquo;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&rsquo;s actually a pretty old drug.

However, the problem is they couldn&rsquo;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.

TARGETED ONCOLOGY:Anecdotally, how have you seen this drug tolerated in the patients who have enrolled thus far? &nbsp;

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&mdash;do not want to lose their hair. Generally speaking, it&rsquo;s very well tolerated.

TARGETED ONCOLOGY: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&rsquo;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.

TARGETED ONCOLOGY:What are the next steps following the METRIC trial?Vahdat:That is a good question. I&rsquo;m not quite sure what the next steps would be. 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&mdash;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 1 set of options—which is chemotherapy, so they&rsquo;re really very limited. Having a drug such as glembatumumab vedotin would expand the options. The expectation would be that, if you expand the options with something that is targeted, you would have better disease control and a better quality of life.

TARGETED ONCOLOGY:What else should the community know about the METRIC trial?Vahdat:If you have TNBC and you really haven&rsquo;t had too many therapies at all, it&rsquo;s really good to speak to your healthcare provider to see whether or not you would be a candidate for this clinical trial. Then, contact us on We would be happy to see if you are a candidate or answer your questions, because it&rsquo;s a great opportunity.

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