Phase II trial tests efficacy of glembatumumab for triple negative breast cancer

Tuesday, December 15, 2015

The phase II registrational METRIC trial is an ongoing randomized trial in triple-negative breast cancer (TNBC) that evaluated the safety and efficacy of the antibody-drug conjugate glembatumumab vedotin. Glembatumumab targets glycoprotein NMB (gpNMB), which has been associated with reduced metastasis-free and overall survival (OS) after a phase II trial correlated gpNMB expression and response to glembatumumab. The METRIC trial seeks to compare glembatumumab and capecitabine in 300 women who have gpNMB-positive TNBC. The trial is still in the accrual stages and aims to gain patients based on the level of gpNMB expression, obtained in the advanced, locally advanced, recurrent, or metastatic setting. Currently, about 40% of TNBC, and approximately 20% of breast cancers overall, exhibit overexpression of gpNMB. Overexpression has historically been associated with reduced survival in breast cancer, small-cell lung cancer, and glioblastoma. Targeted Oncology spoke with Linda Vahdat, M.D., professor of medicine and director of the Breast Cancer Research Program, about the trial. Read the full article here

Photo of Linda Vahdat, M.D.Linda Vahdat, M.D. What are the goals of the METRIC study?

The goals of the METRIC study are to see the effect of a novel antibody drug conjugate called glembatumumab vedotin on progression-free survival in women with triple-negative breast cancer that are high expressors of gpNMB, which is the target of the antibody.

How is the study designed, and what were some of the significant findings?

The design of the METRIC trial is that it is a 2 to 1 randomization to the gpNMB -targeting drug versus capecitabine. The METRIC trial is an ongoing trial. We are very excited; we are going to be accruing a little over 300 patients and the goal is to see what the progression free survival is. Since it is an ongoing trial, we don’t have results yet, but there are two trials, which were done prior to this, in which it was demonstrated that the response rates to glembatumumab vedotin was much higher than investigator’s choice. We are pretty excited about the drug. The timeline on the accrual is probably another year.

What was seen in prior trials with this drug?

There have been two trials looking at glembatumumab vedotin in women who have breast cancer. The first trial looked at women who had metastatic breast cancer who had been very heavily pretreated, and we administered the drug to them.  What they saw was that the response rates in this very refractory group of patients was actually quite respectable. The progression-free survival was pretty good and then they started to look to see if there were any predictors of response out of that trial, which included many different types of breast cancer. They started to get a signal that, perhaps, this [drug] was particularly active in triple-negative breast cancer, which is ER, PR, and HER2 negative and is notoriously difficult to treat. They were able to get, I think, about 15 tumor blocks out of that first trial, and they were able to see that the responses were actually higher and the progression-free survival was even greater in patients who had the gpNMB expression. There wasn’t really a cut point at that point and that is where the EMERGE trial came in, which was a randomized trial of glembatumumab vedotin versus investigator’s choice, but they allowed a crossover, and in that study, they began to really try to understand if having the target was important or not, and if so, what was the cut point.  In that trial, we also saw that there was a much higher response rate in the range of about 30% with the better progression-free survival for patients with triple-negative breast cancer, and even better if they were triple-negative breast cancer and had gpNMB overexpressing tumors. That led to the design and the execution of the METRIC trial, which is the current study, which is ongoing. First of all, the METRIC trial has a control arm, which is capecitabine. It is always difficult to figure out what is a control arm in a randomized trial for metastatic breast cancer when there is no standard sequence of drugs. After much discussion, it was chosen that capecitabine would be the control arm. There is no crossover allowed, which is different from the EMERGE study, and we are looking forward to results.

What is the mechanism of action of glembatumumab vedotin?

Glembatumumab vedotin is an antibody drug conjugate. The antibody part of it targets something called gpNMB, also known as osteoactivan, and that’s is very important for cell migration and invasion. It is linked to a drug called monomethyl auristatin, which is an anti-microtubular drug. The important thing about this is that it delivers the drug directly to the tumor and that is important for certain types of chemotherapy drugs that are too toxic to give by vein. With antibody drug conjugates, generally speaking is that you can deliver a much higher dose of drug to the tumor than you normally would be able to. The hope is that if you can deliver the drug to the tumor that you can kill more cancer cells.  

Were there any toxicities seen with this drug?

It is a fairly well tolerated drug. Side effects that are seen is that it can lower the blood counts, which is probably related to the chemotherapy part of the antibody drug conjugate. Patients can get a rash because GPNMB expression can be in the skin. When you look at sever rash, it is less than 6%; it’s about 3%, and those are pretty much the only side effects. On occasion, there is a low incidence of peripheral neuropathy; I would say in the single digits, but probably below 5%.  

What may be the impact of this drug in the future?

If glembatumumab vedotin is able to show benefit in GPNMB-overexpressing breast cancer, then it would be the first targeted treatment for triple-negative breast cancer. That would be huge, because there are none out there right now. There is no standard treatment for patients that have triple-negative breast cancer. There are many agents that have activity, but there is no direction that we [community oncologists] are pointed in, in terms of what is the optimal sequencing. Triple-negative breast cancer is a very challenging issue not only for patients, but also for clinicians. 

Read more about Dr. Vahdat's triple negative breast cancer research.