Exploring Epcoritamab for Relapsed/Refractory Follicular Lymphoma With Dr. Matthew Hadfield, Dr. Alankrita Taneja, Dr. Tahi Ahmadi, and Dr. Jacqueline Nielsen

Recently, Genmab and AbbVie announced updated results of the phase 1/2 EPCORE™ NHL-1 clinical trial of epcoritamab (epco) for patients with relapsed/refractory follicular lymphoma. In this interview, Dr. Matthew Hadfield and Dr. Alankrita Taneja of the Oncology Data Advisor Fellows Forum speak with Dr. Tahi Ahmadi, Chief Medical Officer at Genmab, and Dr. Jacqueline Nielsen, Therapeutic Area Head for Hematology at AbbVie, about the significance of these results, the benefits of epcoritamab’s subcutaneous administration, management of adverse events, and the future role of epcoritamab in the treatment landscape for follicular lymphoma.

Matthew Hadfield, DO: Good morning, everybody. I’m Matt Hatfield. I’m a current third-year Medical Oncology Fellow at Brown University in Providence, Rhode Island, and soon to be an attending, focusing on phase 1 early drug development. I’m super excited to have this conversation today with Dr. Ahmadi and Dr. Nielsen of Genmab and AbbVie, as well as my colleague, Dr. Taneja. Just to get us started, maybe we can start with some introductions.

Jacqueline Nielsen, PhD: I’m Jackie Nielsen. I’m the Therapeutic Area Head for Hematology at AbbVie. I’m a PhD by training, having trained at Northwestern Medical School in Chicago. I’ve been in Chicago for 25 years or so. I’ve worked on a lot of molecules in hematology, but so far, epcoritamab is my favorite.

Tahi Ahmadi, MD, PhD: I’m Dr. Tahi Ahmadi. I’m the Chief Medical Officer at Genmab. I’m an MD, PhD from Germany. I originally did my training there and was one of the quintessential leaders in the lymphoma field. I came to the States to do my post-doctoral program in Boston, and then I ended up doing my training at the University of Pennsylvania (Penn). Later on, I stayed on as an oncologist faculty at Penn, where I was mainly seeing patients with lymphoma or chronic lymphocytic leukemia (CLL) before I went into industry. Initially, I went to Johnson & Johnson (J&J), where I was involved with a number of drugs that are approved now—namely ibrutinib, which led to its first approval; daratumumab; amivantamab; tucatinib; trastuzumab, tisotumab vedotin at Genmab, where I’ve now been for seven years; and now epco.

Alankrita Taneja, MD: That’s great. I’m Alankrita. I’m one of the third-year Fellows at Roswell Park. I’m also doubly trained in hematology and oncology. I have also signed on for a job offer to lead the Myeloma Program at Jefferson-Einstein in Philadelphia.

Dr. Ahmadi: Oh, you’re coming to Philly. Congratulations.

Dr. Nielsen: Congratulations.

Dr. Hadfield: Congrats.

Dr. Taneja: Thank you. I’m really looking forward to this conversation.

Dr. Hadfield: We have a lot of interesting things to talk about today, but maybe we could start with talking about epcoritamab and its mechanism of action. Obviously, it’s a novel compound that works a little bit differently than immunotherapeutic agents in the past, with some very interesting details. Maybe we can start with hearing a little bit about that.

Dr. Ahmadi: Epcoritamab is a bispecific antibody. It’s on the Genmab DuoBody® platform, which has some unique features that might be important. Broadly speaking, the idea is to create antibody structures that mimic the behavior of immunoglobulin (IgG1) but have fragment antigen-binding (Fabs) against two different targets. In this particular case, one arm of the antibody binds CD3, which is on T cells, and the other one binds CD20, which is on B cells. By having these two arms, you are bringing in close proximity a T cell to a B cell. In the case of patients with lymphoma, this is predominantly the tumor.

The antibody itself is Fc-silent, meaning it doesn’t have any Fc-mediated functions, which is important. By creating proximity, you essentially trigger a reaction that frankly ought not to happen but still does happen. The T cell then starts killing the B cell. It’s a T-cell redirector, as there are many, many others in development that are approved now. It’s a relatively new space, triggered by the recognition that T cells have a profound ability to kill hematologic cells, and it’s a very exciting area.

What is unique about epcoritamab is, beyond the fact that it’s the one that the most closely follows the IgG physiology—meaning that it really looks like an IgG molecule, which is a function of the DuoBody® platform—it is also the first one that was introduced subcutaneously. The reason for that was the observation, in the early nonclinical safety models that we did, that the peak pharmacokinetics (PK) would be modulated in a way that you would avoid it. That was important to us at that point, because we were working from the hypothesis, which ended up being true, that peak PK was what was driving high cytokine release levels, which is the predominant safety issue with this mechanism of action.

Dr. Hadfield: Interestingly, it is such a novel drug that we’re starting to see more and more T-cell engagers and bispecific antibodies being used. Particularly, this is a subcutaneous formulation. In the past, we’ve seen things like rituximab go from infusion to subcutaneous. Have you noticed in—and we’re going to talk about the phase 1/2 study more in depth—but have you noticed any novel toxicities that you would attribute either to the mechanism of action or the delivery mechanism that hasn’t been seen with other similar molecules?

Dr. Nielsen: I guess the short answer is no. The way that drug development records treatment-related or treatment-emergent adverse events (AEs) is that for anybody that gets anything during the course of the trial, it’s recorded. You get things like upper respiratory tract infection because older patients may have a cold. what you generally see is gastrointestinal (GI)–related. You’ll see infections in an older population. The disease itself makes people prone to infections as well, because they’re immunocompromised. Then obviously, when you’re using a subcutaneous injection, you might see a little bit of injection site reactions. But in general, I would say that the AE profile is pretty manageable.

Dr. Ahmadi: Broadly speaking, if you think about T-cell redirection, there are two buckets of AEs that are related to the mechanism of action. One is cytokine release syndrome (CRS), meaning that through the activation of T cells in the process of killing the B cell, it doesn’t really matter. You release gamma interferon, and then what ends up happening is a cascade. Gamma interferon stimulates other cells to release other cytokines. You get this cytokine release, broadly speaking. The symptoms of cytokine release are well understood and characterized. Fever is the first one. If it gets a little bit more extreme, it can be fever and hypotension or fever and a minimum requirement of oxygen. Then the grading follows that logic to the degree that the hypertension becomes more difficult to manage, potentially requiring pressures, or the oxygen demand gets significant. That’s the first bucket of AEs that are related to the mechanism of action. Epco is not different.

The second bucket is an ill-understood phenomenon of neurological symptoms summarized under the term immune cell effector–associated neurotoxicity syndrome (ICANS). There’s no good explanation except the idea that you activate T cells, presumably CD4 for this particular toxicity, and they have some weird interaction that leads to transient confusion and headaches. What we now summarize as ICANS is not necessarily what we used to think of as neurotoxicity. It’s basically now every term that falls under this bucket of the system organ class—headaches, confusion—but it can be problematic, to the point that people are unable to communicate in very severe cases. This has not happened with epco so far.

Then there’s a unique third bucket, I would say, for the CD20-targeting, which is neutropenia. This is true for rituximab as well. There’s some biology that we don’t really understand between CD20-positive cells and neutrophils. So, there are kind of the three buckets. In that range, epco behaves like the other ones in the class. There’s really nothing specific to the subcutaneous administration. It’s not really formulated. Rituximab is formulated; it’s basically a chemical modification that uses an enzyme to allow it to be administered subcutaneously. It’s very similar to the other tumors in the subcutaneous infusion. With epco, it’s purely subcutaneous administration. The antibody is in the same solution as an antibody that would be given intravenously (IV). It is just so potent that the amount of protein that you need to give to a patient is relatively limited, upwards of 48 mg total. You can actually administer that small amount in a very small volume under the skin, and it gets absorbed really well.

Dr. Nielsen: I’ll just reiterate that what we see are really class effects across either anti-CD20 or T-cell engagers. We’ve been developing epcoritamab to be patient-friendly, using the step-up doses to mitigate any grade 3 or 4 CRS or ICANS that we might see. There is an intelligent trial design to mitigate in-class effects.

Dr. Taneja: That sounds great. To add to that, could you describe the trial design?

Dr. Ahmadi: The current data that has led to the registration of epcoritamab in diffuse large B-cell lymphoma (DLBCL), and also the dataset that’s now being submitted to global health authorities in follicular lymphoma, comes out of an expansion quota of the original first-in-human trial. The first-in-human trial was expanding the doses, and then once it settled on the recommended phase 2 dose, it went into distinct populations that would meet criteria for an unmet medical need for the few such B-cell patients who had two prior lines of therapy and are not eligible for transplantation. For follicular lymphoma, this was patients who had also two prior lines of therapy, so third-line patients in both settings. It was broadly understood as patients for which there is no well-defined standard of care.

What Jacqueline was referring to is that all of these drugs use a step-up dosing, meaning they start at relatively low doses, and then in one or two steps, get to the recommended dose to get the full effect of the drug. That is meant to mitigate the cytokine release. In a subsequent iteration of the study, we also generated data that helped us understand how to further improve the safety profile, such that we were able to significantly reduce the cytokine release profile and completely abrogate any evidence of ICANS. A particular PK modeling allowed us to understand that in follicular lymphomas, for example, that a second step-up introduced a more gradual increase over a period of time will fundamentally change the safety profile.

At this point, now the drug has mainly grade 1 CRS, in which patients only have fever. There’s a <10% rate of grade 2, meaning people who require some infusion of fluids, 500 cc. Both of these things are easily managed in an outpatient setting. There’s no grade three, meaning there’s no need to hospitalize. There’s also no ICANS, meaning there’s no risk of potential neurologic toxicities with that step-up dosing. That’s very important, because the ambition and aspiration for this drug from the very beginning, also because of the subcutaneous administration, was to produce an easily administered medicine that can be provided to patients in all kinds of setting, not only in specialized hospitals.

Dr. Hadfield: That’s great. Interestingly, in the phase I side, did you do inpatient admissions for the first few patients? That is becoming such a thing with a lot of these bispecific antibodies and novel natural killer (NK) cell–based therapies, that there are so many inpatient hospitalizations. That’s a unique aspect of this drug that you don’t require that, because it really is a logistical hurdle a lot of people are facing.

Dr. Ahmadi: The reality is this—you have to dial the clock back a little bit. Epco was started in 2018. It was actually the last of the five CD3/CD27s that went to the clinic. The first CD3/CD27 went into the clinic at the end of 2015. At that point, the knowledge base on how to safely manage this set of symptoms that we spoke about, CRS and ICANS, was very limited. All experience came from chimeric antigen receptor T cells (CARTs), where these symptoms are significantly more profound—CRS and ICANS are much more severe. For these very reasons, everyone was mandated by health authorities, for appropriate reasons, to require hospitalization to provide appropriate observation until we started to understand how to better manage these effects, which I think is fair.

Over time, the community in general has learned to better manage this. Also, as we just alluded to, we’ve understood how to better mitigate them through the administration of fluids and steroids in diffuse large B-cell, for example, and through the modification to step-up dosing. Now you’re getting into a situation where the grade and severity are lower. The experience in how to manage this is better, so we better understand how to manage it. It becomes much more realistic to apply this safely. In the end, patient safety comes first. I understand, from a health care resource point of view, it’s a very important question to be answered.

Dr. Nielsen: The short answer to your question is yes. We always try to hospitalize when we don’t understand what the safety profile is going to look like. But the team has done a lot of work moving into a pre-regulatory state to get us to a place where, hopefully, we can bring this molecule into a completely outpatient setting in the future.

Dr. Taneja: Would you like to touch upon some of the major study findings and how they would compare to some of the other T-cell engagers?

Dr. Nielsen: In particular, the NHL-1 study had lots of arms. We’ve already used the DLBCL and large B-cell lymphoma (LBCL) cohorts for our current approval. What we’re discussing today is the follicular lymphoma cohort. Patients in this cohort were very heavily pretreated. We use the term POD24 to describe patients who progress off of chemotherapy within 24 months. In follicular lymphoma, generally patients get a median of five or six years after their first therapy. This cohort of patients was pretty heavily enriched with patients who were either refractory to their first therapy, who were refractory to the two prior lines of therapy, or who progressed within two years. They’re all kind of markers of less indolent follicular lymphoma. These patients were in need of something a little bit stronger, which is why they opted to go on a clinical trial.

In that population, we were able to produce an 82% overall response rate a with 63% complete response rate (CR).In follicular lymphoma, it’s an indolent disease, and you don’t aim even for durability, but CR is a very good predictor of that. We’re very, very encouraged by the rapidity of response. You can see the median time to CR is 1.5 months, which is driven by the first pre-staging of patients. Between that and the step-up dosing, we really think we have something strong we can offer patients, but also in a way that it can be administered across practice settings.

In terms of comparisons to the field, as Tahi stated, there’s no real standard of care in follicular lymphoma, particularly in the third line and for patients with this level of aggressiveness in their disease. Across the practice care settings, you can potentially reach for a bispecific or another T-cell engager. In particular, the CAR Ts come with a lot of logistical challenges, and they’re not available to a lot of patients. There’s also a fair amount of limitations to where you can access CAR Ts in the space. A lot of patients with an indolent disease don’t really want to opt for the level of hospitalization and rigor that is required for moving towards a T-cell engager. I think we have a pretty good option for deeper remissions in some of the most aggressive phenotypes of this disease, and moving forward, potentially all lymphoma patients.

Dr. Ahmadi: I think my only thing to add is, if you think about the class of CD3/CD20s in follicular lymphoma from an efficacy point of view, they tend to behave very similarly. That probably is a reflection of the functionality of T cells in follicular lymphoma, to be honest. Diffuse large B-cell is a little bit easier to see differences between the constructs. There you can see, if you look at the data for all four, epcoritamab has the highest response rate, and the higher CR rate in the cross-comparison. This is always dangerous, cross-comparisons. In follicular lymphoma, they’re more or less the same. But here, I think it’s important to note that with the optimization, the safety profile of epcoritamab is extremely competitive. It’s actually the lowest rate of grade ≥2 for all of them. It’s the only one, at this point, that is administered subcutaneously, which we discussed before, and it has significant advantages in terms of convenience for patients. It’s basically a difference between several hours versus a minute—well, it’s never a minute because you still have to go to the provider—but nonetheless, it’s a significantly more convenient way of administering the drug.

Dr. Hadfield: No, it’s a great point. I mean, at the American Society of Clinical Oncology (ASCO) Quality Care Symposium, there were several sessions focused on time toxicity to patients. With infusion drugs versus subcutaneous drugs, there are a lot of quantifiable ways that subcutaneous administration is better for patients. In infusion centers, there’s less cost of staff and less cost of administration. Those are phenomenal results in a heavily pretreated population. Any plans for further expansion cohorts in other disease states?

Dr. Nielsen: I think we’ve seen proof of concept in most B-cell malignancies. Obviously, we have a third-line approval in DLBCL. We’re moving into second line and frontline with combination therapy, which we’re very, very excited about, and trying to improve the cure rates in DLBCL. For follicular lymphoma, we similarly are moving into earlier lines of therapy with combinations to try to deepen and prolong those first remissions. We just released our data in CLL this year at the International Workshop on CLL (iwCLL), very exciting data in very heavily pretreated patients. CLL has been a disease state that I’ve spent a lot of time in. I’m very excited to have options for patients where there really are no options in the Bruton tyrosine kinase inhibitor (BTKi)/BCL2–doubly-exposed patients. That’s probably not the only place we’re going to land in CLL considering it’s, in my opinion, a better anti-CD20. It could go wherever anti-CD20s are.

Dr. Ahmadi: Broadly speaking, I think the promise of this new class of agents that is emerging, is that it combines the unprecedented—though sometimes the term “unprecedented” gets overused—efficacy results for T-cell engagement. Now, we’re speaking about lymphoma, and we could talk about myeloma too, but the efficacy results for T-cell engagement are without a precedent. There have never been drugs before that had a 60%-80% CR. This is unheard of as a single agent in refractory patients. The promise of this class is that you can actually combine it, in contrast to CAR-Ts, with other modalities. You can combine it with lenalidomide, which we’re doing. You can combine it with chemotherapy, which we’re doing, for the reason that chemotherapy debulks, and now you have better immune control. You can combine it with lenalidomide, because lenalidomide, in some way, enhances T-cell function, and then you get synergism. We have shown that in the clinic already.

As you combine it, you can move it into the earlier settings. The goal is to move this mechanism into the frontline. Together with AbbVie, we are working on what is a very aggressive, very comprehensive clinical development, moving this very systematically along the lines. We have already a phase 3 ongoing in the relapsed setting for diffuse large B-cell. We have a phase 3 ongoing in frontline, in combination with chemotherapy with R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) in diffuse large B-cell. We also just announced that we are going to start working with collaborative study groups on doing a combination in frontline for patients with diffuse large B-cell who are elderly and who are not candidates for full R-CHOP. We are generating data for cardiovascular-impaired patients who are really not candidates for anthracycline in the diffuse large B-cell frontline setting.

Also, we announced that we are going to do a study in the relapse setting with lenalidomide, comprehensively addressing the spaces of diffuse large B-cell. Similarly in follicular lymphoma, there’s already an ongoing study in the relapse setting with lenalidomide/rituximab with data we presented that was really unprecedented. In combination, the CR rate was 98%, which basically means that only one patient on the study didn’t respond. Now we are generating data in frontline in follicular lymphoma. I think Jackie already mentioned that we also have data in CLL regarding the CD20-targeted mechanism. It has a play in all diseases that are CD20-positive. There’s a practicality to how drugs are developed and the time it takes; it doesn’t happen overnight. But the ambition is clearly to position epco as a main mechanism across the spectrum of B-cell malignancies and across all lines.

Dr. Nielsen: I would be remiss if I didn’t say that it’s EPCORE™ “core” therapy. That’s where the team is trying to set the tone.

Dr. Taneja: One last question, if you have the time for it—I was wondering if there were any major exclusion criteria that you had in your trials, or any patients that cannot be considered a candidate for this therapy in terms of their comorbidities?

Dr. Ahmadi: Every trial has inclusion/exclusion criteria; usually in clinical trials, they’re around performance status. Otherwise, I think the only other inclusion/exclusion criteria that’s probably worth mentioning is that, because of unclear impact on the safety, we initially excluded patients who had received allogeneic (allo) transplant. This is something that I think we are now exploring very gradually, where we now allow patients to come on studies who had a prior allo transplant, but they have no existing graft-versus-host disease that requires immune suppression.

Beyond that, one of the main differentiating aspects of these bispecifics is that they’re available and can be administered to patients who may otherwise not be candidates for CAR-Ts because of their frailty, other preconditions that preclude them from getting involved on CAR-T trials, or issues with getting access to CAR-T trials. As a cross-comparison, that’s true for all bispecifics, by the way. The patients who came onto these trials, in many cases, were either not eligible for CAR-Ts, or in about half of the patients, actually had prior CAR-Ts. That’s also the context in which one has to understand this cross- comparison data. It’s a significantly more pretreated, significantly more frail patient population than the CAR-T therapies included in the clinical trials. I think this is the promise, that this is truly a much more egalitarian way of approaching the disease. It’s scientifically very interesting, but nonetheless, a very exclusive approach that can only be provided in specialized centers and to hand-selected patients.

Dr. Taneja: That’s very exciting. Actually, I was listening to another lecture on DLBCL yesterday, and there were some debates about whether some of the bispecifics can be used as a bridge to CAR-T. Do you think that that’s also a possibility for epco?

Dr. Ahmadi: There are going to be all kinds of investigations in the community to figure out how to use these mechanisms for whichever practice you choose to do. I personally would say, that’s probably not the long-term goal. I don’t think that’s going to be the place for the drug, although the general philosophy of drug development is that you provide options so that physicians and patients have different kinds of opportunities to benefit from novel therapies.

Dr. Nielsen: I think to Tahi’s point, over time, we would hope our combination therapies can stand up to the long-term outcomes that we see with CAR-T. There are people who believe in the therapy because they’ve been around long enough to demonstrate outcomes, as we’ve shown, but we need a little bit more time to demonstrate the durability.

Dr. Hadfield: Perfect. Well, thank you both for joining us today. This is really interesting stuff to talk about, and obviously, phenomenal results in a patient population that really needs a new therapy. Especially the subcutaneous delivery mechanism—you can’t underscore that enough. That’s huge for patients, and that’s going to make things easier for infusion centers too. It’s really going to make it more applicable to centers all over the world, as opposed to just in large academic medical centers where they’re more trained to deal with these things. It’s very exciting stuff and thank you both so much for joining us.

Dr. Ahmadi: You’re welcome. Thanks a lot.

Dr. Nielsen: Thank you.

About the Speakers

Matthew Hadfield, DO, is a Hematology/Oncology Fellow at Brown University/Legoretta Cancer Center in Providence, Rhode Island. His research interests include early-phase drug development, novel immunotherapeutic combinations to overcome therapeutic resistance, and predictive biomarkers for immunotherapy toxicities.

Alankrita Taneja, MD, is a Hematology/Oncology Fellow at Roswell Park Comprehensive Cancer Center. Her research interests include multiple myeloma and cellular therapies, and she is passionate about humanism and equitable care.

Tahi Ahmadi, MD, PhD, is the Chief Medical Officer and Head of Experimental Therapeutics at Genmab. He has years of expertise in translational research, strategic product development, global regulatory submissions, and clinical development. He has been instrumental in the development of numerous therapeutic agents, including ibrutinib, daratumumab, amivantamab, tucatinib, trastuzumab, tisotumab vedotin, and epcoritamab.

Jacqueline Nielsen, PhD, is the Therapeutic Area Head of Hematologic Oncology Affairs at AbbVie. She has extensive experience in early drug development, laboratory assays and methodology, basic science, and translational research.

For More Information

AbbVie (2023). AbbVie announces US Food and Drug Administration (FDA) and European Medicines Agency (EMA) updates for epcoritamab (Epkinly®/Tepkinly®) for the treatment of relapsed/refractory follicular lymphoma. Available at: https://news.abbvie.com/2023-11-27-AbbVie-Announces-U-S-Food-and-Drug-Administration-FDA-and-European-Medicines-Agency-EMA-Updates-for-Epcoritamab-EPKINLY-R-TEPKINLY-R-for-the-Treatment-of-Relapsed-Refractory-Follicular-Lymphoma

Genmab (2023). Genmab announces positive regulatory updates for epcoritamab (Epkinly®/Tepkinly®) for the treatment of relapsed/refractory follicular lymphoma. Available at: https://ir.genmab.com/news-releases/news-release-details/genmab-announces-positive-regulatory-updates-epcoritamab

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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