Steven P. Treon, MD, MA, PhD, Professor of Medicine, Harvard Medical School, Boston, Massachusetts, discusses preliminary clinical data from a phase 1b study of mavorixafor in combination with ibrutinib for patients with Waldenström macroglobulinemia with MYDD88 and CXCR4 mutations. These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Hi, my name is Steve Treon. I'm a Professor of Medicine at Harvard Medical School in Boston. I'm also the Director of the Bing Center for Waldenstrom's Macroglobulinemia based at the Dana-Farber Cancer Institute in Boston, Massachusetts.

A number of lines of data excited us about doing this study. The first, of course, was the discovery of the CXCR4 mutation in Waldenstrom's macroglobulinemia (WM). This is actually a fairly unique mutation in this malignancy. You do see this mutation occur in the germline of patients that are born who have so-called WHIM syndrome, W-H-I-M.

In that case, what you see is individuals having recurrent infections. They have this hypogammaglobulinemia. They get warts. They get what's known as myelokathexis, which is the neutrophils actually sit in their bone marrow instead of circulating around and fighting infection.

In Waldenstrom's patients, these mutations occur -- same domain, the C-terminal domain of CXCR4 -- but they are confined really to the tumor itself. This is unique, as I said, because you do not really see this mutation occurring in many other B-cell malignancies. We do see a splatter here and there in diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), but they're fairly unique to Waldenstrom's. About 40 percent of all patients carry it. That was the first important data point. It was discovered in our laboratory, thanks to whole genome sequencing, this along with the MYDD88 mutation which occurs in about 95 percent of all patients.

CXCR4 does something very interesting, which we also discovered along with others. That is that it creates resistance to drugs and BTK inhibitors, very importantly. It causes a delay in response to ibrutinib, but it also affects the depth of response. You also see that patients who carry these mutations tend to progress earlier.

A very similar observation has also been made with zanubrutinib, where the depth of response also is affected by CXCR4, so we know that this is a class effect. The intrigue has been can we drug CXCR4 when the mutation exists.

The first study that we undertook to do this was a phase 1 study using ulocuplumab. This is a monoclonal antibody that targets the CXCR4. It binds to it. It prevents its ligand, CXCL12, from binding.

It was a very exciting study using this monoclonal antibody. We were able to show that we could get similar levels of clinical activity as one would see in somebody who did not have the CXCR4 mutation. We got rapid responses. The depth of response was there, very quickly, in fact. Even at 2 years, the progression-free survival (PFS) looked like somebody who never had the mutation. This is what excited us about this trial.

Unfortunately, BMS decided to discontinue ulocuplumab's development because they didn't have a signal in other diseases they were looking for. Nonetheless, the science was there to help us get excited about doing this particular trial.

First of all, we were excited about mavorixafor because it's oral, unlike ulocuplumab, which had to be given by intravenous injections. This really gave us the opportunity for all-oral therapy, along with ibrutinib. To me, this was exciting, going forward.

The tolerance of the 2 drugs also proved, so far, to be good. We did have some AEs, but it's hard, sometimes, distinguishing the AEs that are attributed to ibrutinib in a combination. That is a very important learning point today.

The IgM levels have come down beautifully in the patients who have been on treatment long enough for us to get a sense of it, and the hemoglobin levels, which is important because most patients who have Waldenstrom usually are anemic. We've seen a really nice increase in a very quick period of time.

All in all, the message so far is a good one, that it looks like the tolerance is there, barring some of the AEs that we did see. The escalation is going well.

This is still a study in progress, looking at getting to the highest dose level in an intrapatient escalation schema, and seeing the nice impact so far on IgM and hemoglobin. All is good. We're still learning. We're excited to see the study to completion.

This is an exciting study because it yet reinforces the idea that we can use whole genome data to advance therapy in a very specific and personalized way.

What's exciting here is that CXCR4 mutations, people are starting to really understand their importance with a number of therapeutics affecting Waldenstrom's. The idea that we can actually target now CXCR4 in a very specific way is exciting.

As we move forward, what's going to be important is to do the genotyping for patients to understand if they have the MYDD88 mutation, to understand if they have the CXCR4 mutation, and then plot therapy targeting these mutations in a very specific way.

I like what has happened with Waldenstrom's, that we have now a playbook that comes right out of the whole genome. It's a good example of how we can leverage genomic data to advance therapy and even personalize it.

That's why I think for our clinician colleagues out there, there's a very important message to this study and to understanding how we can target CXCR4 in a very specific way.

What's exciting for us is that this phase 1 data, we're going to leverage in a number of different ways. The most important way is to really look at a randomized phase 3 study as a successor.

Understanding what the safety data and tolerability, the PK data that will come out of this study, the pharmacodynamic data that will come out of this study, that will give us useful biomarkers, will help us inform this phase III study that we anticipate will follow but will give us, at the end of the day, the answers that we want, to see the specific impact of mavorixafor's addition to ibrutinib.

I'm excited because ibrutinib is here to stay, as are BTK inhibitors. We now have zanubrutinib also approved for the treatment of Waldenstrom's. We know that acalabrutinib is also a very active drug. We also know that pirtobrutinib, even with the early data, is active.

BTK inhibitors are here to stay. As a result, what we can do to optimize their usage becomes all the more important. This is a good trial because it will be the first to inform us of a credible way to optimize therapy going forward.