Glembatumumab and the Phase IIb Registrational METRIC Trial: Q&A With Denise Yardley, MD, and Linda Vahdat, MD

December 15, 2015

The phase III METRIC trial is an ongoing randomized trial in triple-negative breast cancer that evaluated the safety and efficacy of the antibody-drug conjugate glembatumumab vedotin.

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.

The trial has a primary endpoint of progression-free survival (PFS), and final data analysis will occur after 203 PFS events. 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.

Both Denise Yardley, MD, a medical oncologist at the Sarah Cannon Cancer Research Institute in Nashville, Tennessee, and Linda Vahdat, MD, professor of Medicine, director of the Breast Cancer Research Program, chief of the Solid Tumor Service, Weill Cornell Medical sat down with Targeted Oncology to further explain the phase IIb METRIC trial and the importance of glembatumumab in TNBC.

Denise Yardley, MD

TARGETED ONCOLOGY: What are the goals of the ongoing METRIC study?

YARDLEY:The METRIC study was a follow-up study on the results that came from the EMERGE trial. The EMERGE trial was a trial that was looking at all subtypes except for the HER2-positives, so ER-positive and triple-negative patients. It was looking to evaluate glembatumumab (CDX011) at that time against a panel of different treatment options for patients and how the signal of activity in the triple-negative population where, against investigator’s choice of an agent in the triple-negative population, had a median PFS advantage. It was about 3.5 months and a median OS advantage of about 10 months, compared with 1.5 months and 5 months, respectively, in the investigator’s choice [arm].

Now it’s a novel drug, an antibody conjugate, which seems to be a growing and emerging class of drugs. The target for glembatumumab is gpNMB expression, so the patients on the trial had to have their tumor epithelial expression greater than 25%. It seemed to be from the EMERGE trial that the triple-negative population had expression of about 40% and so that was the premise to go into the METRIC trial.

The METRIC trial was [a] less heavily pretreated [population]. Patients can have up to two prior [medications], they needed an anthracycline and a taxane. All patients have to have their tumors tested that are samples from the advanced-disease setting and [the samples] have to demonstrate the gpNMB expression, which is what the drug antibody is targeted to. This novel drug antibody that is delivering the monomethyl auristatin E and chemotherapy cytotoxin via the delivery of the target of the gpNMB then is randomized against capecitabine. That trial is ongoing, and hopefully we’ll be able to replicate the strong signal from the EMERGE trial.

Why was capecitabine chosen as the control arm?

Trying to look at the taxane and anthracycline pretreated patient population, which is a stipulation of the trial, and looking at a drug that had an indication in metastatic breast cancer in up to two prior lines of therapy, capecitabine really emerged as a drug that’s frequently used in that setting and has that FDA-labeled indication.

Is there a standard treatment for this situation?

There isn’t a standard cytotoxic that’s approved in that space, or even multiple drugs. When we look at taxanes that are heavily used in this patient population, that was a stipulation that patients had to have [in the study]. If they didn’t see it in the adjuvant [setting], they had to have had it in the metastatic setting prior.

Can you provide information on glembatumumab

It’s a drug antibody conjugate, so [it is] very much in this evolving class of new drugs where we have a chemotherapy linker and then a target. The antibody target is this gpNMB expression that’s found in multiple different tumor types. It’s not breast restricted—we’ve seen it in melanoma and lung cancer—but overall in breast [cancer] it’s about 20% to 30% but has a preferentially higher expression in about 40% in the triple negative [patients]. All patients are screened for that [expression], and the drug antibody conjugate has the antibody that targets the gpNMB. With the linkers, [the drug] is able to be internalized, where it then releases the chemotherapy cytotoxic agent internally into the cell and really gives that second kick in terms of the cytotoxic delivery into the cell.

Is this the only targeted treatment in TNBC?

There are growing other drugs, a lot [of agents] in phase I, but it’s [glembatumumab’s] the first real drug antibody conjugate that is far along into a trial now and is specifically targeting gpNMB. There is a lot of enthusiasm based on the signals seen from the EMERGE trial, so that’s where we selected it [the target]. It’s active in other tumors but the expression of the gpNMB, which is used as a screening, has less prevalance in the ER-positive [population]. That was the rationale for moving forward with the highest expressions noted in the triple-negative population.

If glembatumumab were to continue to show positive activity in TNBC, what impact could it have on treatment?

I think it would be able to deliver a targeted therapy for that patient population. It’s such a huge unmet need. We recognize that it is a very aggressive cancer that responds to cytotoxic agents in the absence of an identified biologic. There are a lot of different signals, and this would be a way of harnessing both the specificity of the gpNMB expression, localized to a higher degree in the triple-negative population, and really be able to target delivery of the chemotherapy, which has some standard side effects, but it’s very targeted and specific for tumor delivery.

Are there any concerning adverse events?

Common side effects we see are a little bit of a rash, some of the patients have experienced neutropenia. There can be some peripheral neuropathy, typically with cumulative doses, but because of the packaging and delivery of the chemotherapy intercellularly, that doesn’t seem to be such a phenomenon. Fatigue, rash and neutropenia are the most common [adverse events].

This trial is ongoing. Where is it currently?

The trial is continuing accrual and, now that we’ve been able to add prescreening and identify patients by the gpNMB expression, we’ve made some modifications using the definition of triple-negative with the hormone receptor positivity as less than 10%. I think accrual has really picked up and has gotten on to a lot of different radars and has had a lot of publicity. It’s now not quite halfway [accrued], but a good start toward that.

Linda Vahdat, MD

TARGETED ONCOLOGY: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.