iwNHL 2025 | The use of bispecific antibodies and other immunotherapeutics in early lines of treatment for NHL

Martin Hutchings

Hello, my name is Martin Hutchings. I’ve just had the pleasure to chair together with my good colleague Elizabeth Budde an interesting session about bispecifics and other immunotherapeutics in the early lines of treatment of lymphomas. Very good session with excellent pictures and a very lively discussion and debate afterwards. Before we get into the details about this session, I’d like you to introduce yourself, my fellow panelists.

Elizabeth Budde

Hi, my name is Elizabeth Budde. I’m a hematologist from City of Hope National Medical Center.

Lorenzo Falchi

Hi, I’m Lorenzo Falchi. I’m an assistant attending in the lymphoma service at Memorial Sloan Kettering Cancer Center in New York City.

Sameh Gaballa

And I’m Sameh Gaballa. I’m an associate member at Moffitt Cancer Center in Tampa.

Martin Hutchings

So just to kick us off, we began discussing the usual suspects, I would call them the five CD3/CD20 bispecifics that have been under development for some time. And then we went on to discuss some of the newer kids on the block. And one of those have just recently been baptized, which is surovatamig, which you talked about. And perhaps let’s begin with your take on this session.

Sameh Gaballa

Yeah, no, absolutely. So it was a great session. We had a lot of very interesting presentations. I presented the data with AZD0486, which is a bispecific antibody. But unlike the others, this is a CD19/CD3 bispecific antibody. And so far, so we have data from the Phase I study looking at the step-up dosing, as well as the patients with diffuse large B-cell lymphoma, as well as follicular lymphoma. Now, these patients were CD19 positive were enrolled on the study, and we’re seeing very promising efficacy, both in the diffuse large B-cell lymphoma, but also very high CR rates and MRD negativity in the follicular lymphoma. And now the follicular lymphoma is actually going, is enrolling in the Phase II study. And hopefully soon we’ll have the recommended Phase II dose for the diffuse large B-cell lymphoma for the Phase II as well.

Martin Hutchings

So before we go to talk about combination studies, which was to a high extent the scope of our session, just one question about surovatamig and its development. So these immunotherapies rarely lead to dose-limiting toxicities. They have a lot of toxicities, but rarely dose-limiting. So dose-finding is largely based on early efficacy signals and pharmacodynamics. So surovatamig has been developed in separate Phase I studies for indolent and aggressive lymphomas, right, leading probably to different recommended Phase II doses.

Sameh Gaballa

So, yeah, I mean, it was an overarching large Phase I study with many different histologies. And then there was expansion phases, as you said, separately for the diffuse large B cell and the follicular lymphoma. It’s just that at the current dose level of 7.2, we were really seeing very high response rates. And then with the higher dosing, it didn’t really make sense. So I think that’s the right dose for the 7.2. For the follicular lymphoma, I mean, but for the diffuse large B-cell, I mean, we’re still seeing increased efficacy with higher doses. So I think this is the part that we’re still trying to, to figure out what’s the right dose for the diffuse large B-cell lymphoma. Now, in terms of toxicity and dose-limiting toxicity, obviously, I think one of the things that we’re still trying to understand is what’s the best schedule and what’s the best step-up dosing approach to minimize CRS and neurotoxicity. And I think that’s kind of like the main challenge at this time.

Martin Hutchings

So Dr Budde and Dr Falchi, looking back at the development of the CD3/CD20 bispecifics, which went through Phase I now quite a while ago. Seeing that probably we have some kind of bell-shaped dose-response curve, was it a mistake to have a one-size-fits-all recommended Phase II dose for these drugs?

Lorenzo Falchi

I’m going to venture to say probably not. And the reason for that is if you go further back to when rituximab was developed, it was developed much like we developed chemotherapy by body surface area, which is currently an antiquated way of going about it. Even its successor, obinutuzumab, is a flat dose drug. And we know this because obviously the pharmacokinetics of these drugs are driven by the reticuline and ethereal system and not by the liver function or kidney function. And so really what we’re looking for is to get enough dose in a body organism system as opposed to enough dose for that particular body. There is certainly inter-individual variability, but I think at the doses that we’re using, considering the potency of these drugs and also considering the quote-unquote self-amplifying mechanism, I think once you identify a dose with a PKPD population pharmacologic analysis, I think that’s quite adequate for both.

Elizabeth Budde

I’m just going to say that a lot of this early study determining the doses based on receptor occupancy, and which, you know, in a population you might be able to define, but down to individual patients, as we know, these are recruiting immune cells, which are the effectors, you know, that how well the drug works, could vary from patient to patient, from disease burden by how many target shots are there. So I think it’s really hard to define an ideal dose level for most patients. And also in the very competitive landscape, I’ve been thinking a lot about this, such as mosunetuzumab, epcoritamab, and also odronextamab has a luxury to really test out. And one of the reasons there’s some of the newer drugs that really fail is really because people are in a hurry to develop, trying to get to the higher dose, see more toxicities. But I think we can safely say that’s really the dose response curve is really not linear, which makes it very difficult to define what is the true RP2D.

Martin Hutchings

That makes sense. And even if there is a kind of bell shape, that bell will be different looking and positioned differently from patient to patient. So a flat dose is a nice and easy compromise. So most of this session was about early alliance of treatment. And logically, when we’re talking first and second line combination studies. So we’ve seen almost hundreds of combinations presented in the last couple of hours. Which ones are you most enthusiastic about?

Lorenzo Falchi

Well, I focus my talk on epcoritamab, having worked with, in reality, all of the bispecifics, at least the CD20-targeting ones. What excited me about the data that I’ve been involved with is, well, the first thing is, I think route of administration makes a difference. And as we know, epcoritamab was conceived as a subcutaneous from the start. Mosunetuzumab’s development is moving towards that direction. I’m a little bit unclear about glofitamab, we’ll see. But it does allow for greater combinability and versatility of the drug because it’s, simply speaking, less share time and you’re more able to combine it right up front. Glofitamab has a first dose in at least four hours, depending on CRS, even longer than that. So I think that is the first ingredient of what really then excited me, which is the ease of incorporating a bispecific like epcoritamab in currently existing standards of care, which from a developmental and regulatory point of view is a leg up, if you will. But the part that excited me even more is that although these were, if you will, low-hanging fruit combinations because the standards of care are existing, in particular, in follicular lymphoma, the combination with lenalidomide, I found it very rational. And there are pre-clinical data to support that. It bore out in the clinic as well and we just recently published the results of the epcoritaman R-squared in follicular lymphoma second line and beyond. And the results were really solid with you know complete responses seen in close to 90% of patients close to 80-85% of patients disease-free at two years. These are not numbers that we’re used to seeing in patients with the multiply relapse follicular lymphoma. If you think of the augment cohort, where more than 40% of the patients are progressing within the first two to three years. So what excited me ultimately is that I think that the incorporation of bispecifics into existing paradigms, we’re probably shifting those paradigms. We’re looking at follicular lymphoma patients having three, four, five years duration of remission in the third, fourth line of therapy, which is not something that we’re used to seeing. And ultimately, the joy of communicating and transmitting that to our patients is really what this all boils down to.

Martin Hutchings

And in a few years, will we see the end of our bendamastine and first-line treatment of follicular lymphoma?

Elizabeth Budde

Certainly hope so. I think we’re really moving, you know, about this bispecific, you know, moving towards the earlier line use. I’m really hoping in the future chemotherapy will be obsolete. As we know, chemotherapy is not just as acute toxicity, but also long-term toxicities. So for follicular lymphoma, I think it’s really, given the disease nature, we’ll probably see more chemo-free regimen use, earlier line use. For DLBCL, I’m actually pretty excited about different bispecific combinations moving into second-line space. NCCN guidelines already listed a few of them combinations with chemotherapy treatment or with polatuzumab. So the advantage of having a bispecific in second-line is really tailored for user-friendly, off-the-shelf. We all have those patients who might be a CAR-T candidate, but you really can’t get a CAR-T because you need to make the product first. So this bispecific combination really provides, I guess, a realistic hope for those patients. And those patients will be able to get access to this after-shock treatment. So I think a way to give this medication, teach the community, especially community setting, to use these medications can certainly improve the outcome of patients.

Lorenzo Falchi

And the landscape’s changing so much. I mean, there are four, actually five, randomized controlled trials in frontline follicular testing bispecific-based combinations versus standard of care. If you take one of the Olympias out that’s having chemo in the control and the experimental arm, the others have a chemo-free arm as the experimental arm. And if one or more of those studies are going to be positive, I think that’s perhaps the largest paradigm shift. So I agree with Liz. This is a really exciting time.

Martin Hutchings

So shifting to the large cell lymphomas, if you allow, we see first-line studies as well, some recently completed, some still ongoing. There, in that space, at least not in the younger and fitter patients, we’re not quite abandoning chemotherapy yet. And R-CHOP or something like R-CHOP seems to still be the standard of care in these randomized studies and the backbone also of the experimental arms. Does that make you joyous or would you rather have taken a larger leap towards an immunotherapy-based treatment rather than adding immunotherapy to standard chemotherapy?

Sameh Gaballa

Yeah. So R-CHOP has been hard to beat, you know, over the years and decades. But I think there is obviously emerging data. We just saw in the summer the data with glo-Pola-R and in the elderly patients it looks very exciting. But obviously, so R-CHOP really works and it works well but it’s not the most tolerable treatment for a significant number of patients which are older. So like 80 and above. Those are typically where the most unmet need is. So I think if we’re able to come up with a combination treatment that is building on that backbone or going with some of the novel combinations without chemo, meaning combining it with polatuzumab or some other agents, lenalidomide, there’s a lot of space to look there. But I think eventually, you know, we would want to move away from chemotherapy or at least have an option that is chemotherapy-free without doxorubicin. There’s a lot of patients that we all see who come in, they have like, you know, cardiac issues or they have poor performance status. They cannot tolerate even mini R-CHOP. And the goal there is really to find something that, you know, can be well tolerated. And I think the bispecific combined with other novel agents, you know, we’re not very close yet, but I think this is where we’re probably going to be moving within the next five years or so.

Martin Hutchings

And the increased efficacy might, upon approval, which I guess we all hope for, allow us in the future to experiment with shorter duration of therapy, perhaps taking out individual drugs, like we’ve done in other diseases after the introduction of more effective agents.

Sameh Gaballa

Exactly. And then, you know, with MRD data, we could probably extrapolate some of the PFS of what it’s going to look like, you know, early on. We’re having, you know, better tools now at looking at this. You know, phased seq looks very, you know, very promising. So I think, you know, with better tools at trying to early on to assess how deep the response is, maybe that would guide us with how future trials will go.

Lorenzo Falchi

I’m going to put a little controversial or challenging point to that because I take all these points and I agree with them. There have been experiences with single agent or single agent plus non-chemo, just like the R-Glo-Pola or targeted chemo, in populations where you can do that because the existing standard of care is not optimal, and that’s the elderly frail, anthracycline-ineligible patients. But single-agent bispecifics are just really not enough in this population. Their response rates are not high. Durability remains to be demonstrated with longer follow-up. So at a minimum, combinations would have to be the way to go. But I would contend that when you start looking at the COALITION data for glofitamab, when you start looking at the Epcor-R-CHOP data in high risk, these are high risk patients and we’re likely to cure in excess of 90% of these patients. That’s a really high bar for a, yes, existing, but perhaps not massive long-term risk in these patients. So I think that while efforts need to continue to be made to optimize, perhaps try to find that edge or find the right patient subsets. I think anthracycline-based chemotherapy as a backbone is going to be not easy to replace in these subsets.

Martin Hutchings

But we are moving a little bit closer perhaps to a situation like advanced stage Hodgkin lymphoma where we’re getting close to 100% and the next job is to reduce without losing efficacy, right?

Lorenzo Falchi

That is absolutely a great point. We at MSK are doing a study called the GLORA study that’s in an elderly, frail population, but it’s starting with a glofit-pola two cycles and then deciding on the number of R-CHOP cycles depending on the response after two cycles. And the results hopefully will be presented soon. That’s an attempt at doing exactly what you’re describing, which I agree might just be the path forward in a situation where curative intent is the goal and the stakes are so high.

Martin Hutchings

So we’ve been discussing chemotherapy combinations. In our session, there was a lot of talk and discussion and debate also about non-chemo combinations, about ideal partners for the immunotherapies, post-immulatory, you mentioned lenalidomide, companion drugs that might circumvent mechanisms of resistance. And because these discussions were so interesting, we actually went 10 minutes over time. We will try in this roundtable to not repeat that exercise. So I think with this, we should wrap up. And thank you very much for your attention and for your participation.

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