Epcoritamab Approval Expands Treatment Armamentarium for DLBCL

Tycel Phillips, MD, associate professor, Department of Hematology and Hematopoietic Cell Transplantation, Division of Lymphoma, City of Hope in Duarte, CA, discussed the utility of epcoritamab in diffuse large B-cell lymphoma and the potential impacts the drug's recent approval will have in the community oncology setting.

Transcript

Can you describe the mechanism of action of epcoritamab?

Epcoritamab is part of a class of drugs called bispecific T-cell engagers. In essence, epcoritamab has 2 binding epitopes, 1 to CD20, which would target malignant or normal B cells, and the other CD3, which targets our T cells. Upon engagement, epcoritamab sort of brings the T cell and the B cell into close proximity, which allows the T cell to sort of release proinflammatory cytokines, which hopefully kills off, in our case, the malignant B cells, or cancerous B cells and induce cell death. So, with each of these infusions, we are causing some T cell stimulation, which induces hopefully more and more of these T cells to engage the tumor, and ultimately leading to response—which is quite different from what we typically see with chemotherapy, which, in essence, is something that just damages DNA of fast-growing cells. So, different mechanism of action from what we see from chemo, and potentially has an avenue of causing efficacy in patients who may be refractory to chemotherapy, as the cancer cells will find ways to sort of avoid being killed off by the chemotherapy approach, which, although we have very, very different quantities and qualities of chemotherapy drugs, I mean, they all in essence function in very similar ways as far as how they cause cell death.

How can epcoritamab help patients who cannot wait for CAR T-cell therapy?

Well, I think it's 2-fold. It's not even those who can't wait—as I mentioned, there's quite a few patients who can't even get access to CAR T. With the data we have from epcoritamab, we do have about a 60% overall response rate and a CR rate somewhere a little bit above 40%, which is a complete response rate for those who are CAR T–naïve. Ideally, if you can get a patient to CAR T, you should, but for those who can't for the various reasons we discussed, whether it's location, socioeconomic-wise where they can't have a caregiver with them for the 30 days required for CAR T, or they just can't take off work or anything else that comes with requirements for CAR T, these could be options for those patients, with the hope that you can get durability of response. That's one thing we don't have right now is the durability data on epcoritamab and how long patients will stay in remission. And potentially, if any of these patients are potentially cured. But specifically to your question, the drug wasn't necessarily studied as a bridge treatment to CAR T. I mean, we have data regarding its use in patients who had not received CAR T and its use in patients who have previously failed CAR T. But as a bridge therapy, I think that's an area of research that's being explored for this patient population. But we really don't have any clear-cut data about how effective it will be as a bridge therapy and sort of what he would do to the CAR T-cell product once you collect after epcoritamab.

How does the side effect profile of epcoritamab compare with other treatments for DLBCL?

The easy answer is with chemotherapy, it doesn't really compare. Because at least with this, we don't see the nausea, the vomiting, the early onset cytopenias, the significant fatigue, hair loss, neuropathy, or mouth sores that we typically see with chemotherapy. But it does have its own unique toxicity profile, mainly being what we call cytokine release syndrome, or CRS, and that is a based on sort of those poor inflammatory cytokines released when the T cell engages with the B cell with the help of epcoritamab. What you'll see is elevation in temperature—fever is usually the first indicator of CRS. Thereafter, you can see alterations in blood pressure and breathing difficulties.

The side-effect profile is very similar to what we see with CAR T. The main points that we know with CRS and ICANS with bispecifics compared to what we see with CAR T, specifically with CRS: the onset appears to be a bit earlier, the duration appears to be not as long, and we don't necessarily see as many grade 3 or 4 cytokine release syndrome events, which is good, especially given that these drugs will hopefully be in the hands of community physicians who don't necessarily have access to an ICU, per se, or necessarily have significant experience with managing cytokine release syndrome. Albeit grade 1, we typically can manage very easily with steroids and sometimes with just antipyretics. Grade 2 is when you tend to sometimes consider use of a drug called tocilizumab, which is an IL-6 [inhibitor used prior to] CAR T. Again, because of the ability to have to store tocilizumab, that may sometimes require a bit more escalation of care because that is generally not something we can give in an outpatient setting.

Now when we look at ICANS, the ICANS events are very low when we look at bispecifics compared to CAR T. The events can still happen, but it's generally not something that's a major concern for the bispecific antibodies. Because of the nature of how by specifics work, we also do run into issues with infections, because again, they are very good at depleting normal as well as malignant B cells. And obviously, if our B cells are depleted, we do run into issues as far as viral infections and other things. And with some of these drugs, we have maybe seen some late-onset neutropenia, which also increases your risk of bacterial infections. But again, these profiles are a bit different from what you typically expect with chemotherapy. And because of some of the unique nature of CRS, this is something that will be a bit of a learning curve for all physicians when they eventually start using these bispecific antibodies, especially those who have not had previous experience with dealing with these types of treatments from CAR T therapy.

Can epcoritamab be administered in the community setting?
I think the whole premise of these bispecific antibodies, besides reducing the time to treat that we sometimes see with CAR T with the vein to vein—from the collection to when you get the manufactured cells back—is the fact that you would hope that these drugs, the bispecifics, would be able to get into more places than what we can with CAR T, which are limited to therapy centers, they have to be accredited to give CAR T. But that's going to take some time and a level of comfortability with dealing with the adverse event profile. Because again, CRS [and] ICANS are unique and things that we don't typically or have seen with some of these other sort of treatments that are available in the community. It's very different from the immune infusion reaction we see with rituximab or some of the other sort of CD20 antibodies. But it's also different from tumor lysis syndrome, from what we see with venetoclax.

I'm bringing these up as examples, as these are also obstacles that community physicians had to overcome to start giving these drugs on a more daily basis. But they did, and they use these drugs quite readily. So, with an expected learning curve, I expect these drugs to be used quite readily in most community centers as they get more comfortable with the side effect profile and more comfortable being able to predict who will have issues and who won't. The good thing with CRS and ICANS, at least from what we're getting from these studies, we are getting very good at predicting when these events are most likely to happen. Based on the different bispecific antibodies, specifically with epcoritamab, it seems that most of these events happen on cycle 1, day 15, which is when you get the first full dose.

So that will allow them to plan more accordingly [and say], “Okay, 61% of patients are going to have CRS on this day, so this is likely when I need to start planning for sure.” Albeit you do need to be on lookout and aware of these events happening prior. But again, the majority of the patients, if they're going to have a problem, it will be on that day. With the other bispecifics, the profiles are a bit different, but it’s just keeping in mind what drug you're using and when you would [most likely] expect CRS to happen and sort of what are your mitigation plan. But as I said, I would expect within a matter of years that community physicians will be very comfortable with these drugs and will be using them, because I do think they will be quite effective and will provide quite a bit of benefit for our patients, whether either in CAR T settings where they fail CAR T or they can't get the CAR T, or eventually as we mentioned before, based on if we get more data, as a bridge to CAR T. But I do think they will provide a level of treatment that we don't necessarily have with some of these other drugs that are currently available today.