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Fixed-Duration Epcoritamab Combination Therapy for Relapsed or Refractory Follicular Lymphoma and Pre-Transplant Strategies for GVHD post-HSCT
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- [00:02]
A
Welcome to the American Society of Hematology Conversations with Blood Authors. This Blood podcast episode is hosted by Dr. Laurie Sen. She discusses fixed duration epcoritamab R2 drives favorable outcomes in relapsed or refractory follicular lymphoma and pre Transplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues Ameliorating GVHD post HSG with corresponding authors Dr. Lorenzo Falci and Dr. Robert B. Levy.
- [00:39]
B
Hi, I'm Laurie Sen, Podcast Editor at Blood and Today I'm joined by Dr. Lorenzo Falci from Memorial Sloan Kettering Cancer Center. He's the lead author of a New Blood article entitled Fixed Duration ebcritamab R Squared drives Favorable Outcomes in Relapse to Refractory Follicular Lymphoma. Thanks for joining us today Lorenzo.
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C
Thanks for having me Lorenzo.
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B
Perhaps you can start by giving us some background on the role of bispecific antibodies in the treatment of relapsed refractory follicular lymphoma.
- [01:12]
C
Bispecific antibodies are a class of transformational drugs in the landscape of B cell non Hodgkin lymphoma at large, but certainly have played a major role in reshaping the treatment paradigms in follicular lymphoma, particularly in relapsed refractory disease. This T cell based immunotherapies co target a tumor antigen and a T cell antigen at the same time and so mediate very powerful cytotoxic T cell killing of the target cells, in this case lymphoma tumor cells. These drugs really have had a very profound impact since the very early data of the first in class drug which is Mosanetuzumab and it was immediately clear already from dose escalation portions of the phase one studies that there certainly was power to these drugs in terms of ability to induce responses, including deep complete responses. And then with longer follow up of the pivotal trials we really seen very substantial single agent activity as measured both by response rate but also duration of response and progression free survival. And I think we are starting to shift the kind of old dogma or old paradigm of lower chance of response and shorter duration of response with each subsequent therapy for these patients where we're now seeing higher response rates and perhaps longer response duration in patients in their third, fourth or fifth line where we wouldn't have expected such brilliant results and this was through the single agent activity then obviously these are drugs that we know very well by now and are very easy to combine. And there's a plethora of combinations that stem from those very early promising data.
- [02:57]
B
So in the context of this phase two trial, can you provide the rationale for why epcoritamab is being combined with lenalidomide and rituximab Here?
- [03:06]
C
Epcoretamab has been combined with a number of standards of care for patients with B cell lymphoma in the multi ARM APCOR NHL 2 study. And this, this one in particular is ARM 2 of the trial. And when we were looking at all those arms, this arm immediately captured my interest because lenalidomide is an immunomodulatory drug that's known preclinically to be able to restore the immune synapse. And the idea of reinvigorating T cell efficacy and then engaging those reinvigorated T cells with a bispecific antibody, certainly very enticing, at least on paper. So there was really a clinical trial idea to test that hypothesis in patients. The addition of rituximab, I think, had a couple of different reasons. One, the most perhaps obvious one, is that rituximab and linolidomide is an internationally accepted standard of care for the treatment of patients with recurrent follicular lymphoma. But also the addition of rituximab was shown preclinically to not interfere significantly with apkaritamab's pharmacodynamic cell killing effect at the dose that we would predictably use in the clinic. So those sort of preclinical premises form the basis for this triplet combination, right? Rituximab, ebkaritamab and lenalidomide in a large phase one, two international trial.
- [04:30]
B
Can you describe the overall study design of what you're presenting in blood and the key findings?
- [04:36]
C
The study was relatively simple. The rituximab and lenalidomide portion of it was modeled exactly after the Augment clinical trial that established rituximab and lenalidomide as the standard of care care for relapsed follicular lymphoma. So rituximab weekly in the first month and then monthly up to cycle 5 and lenalidomide at the starting dose of 20mg for three weeks on one week off. I've recycled to a total of two years of therapy, but only 12 cycles of lenalidomide. Ebkaritamab was given weekly for the first two months or three months, depending on the sub cohort of the study that we analyzed and then it was given monthly thereafter. And as I said, we covered two years of therapy. The initial findings for the study were already immediately very promising. Even while we were enrolling the patients, it was clear that there was very significant efficacy. Most patients achieved an objective response and most of those patients achieved a complete metabolic response. And overall, out of the 108 patients we enrolled in the study, the overall response rate was 96% and the complete metabolic response rate was 88%. It was very reassuring to see that these figures were really recapitulated in select patient subsets, including those with pod 24 with primary refractory disease or double refractory disease. We have a follow up that's relatively substantial for this clinical trial at 28.2 months. And the median duration of complete response in that cohort is 82%, with shy of 80% progression free survival for the same patient cohort. So these are again numbers that we were very encouraged to see. And that duration of response also kind of panned out across different patient cohort, different risk levels. The safety side of our findings was also in a way reassuring because yes, there are side effects, yes, there are grade three or grade four side effects, but primarily these are the ones that we would have expected based on each individual component of this treatment. And these are primarily cytokine release syndrome and injection site reactions for apkaritamab and then the neutropenia, diarrhea, skin rash, as we are used to seeing with rituximab and lenalidomide. But we didn't see synergistic adverse events, if you will, that we didn't see a particularly worrisome signal really anywhere. So, yes, it's a treatment that needs to be handled with care, but we certainly had a very short learning curve and the results, I think justify that safety profile as well.
- [07:18]
B
So I guess one of the toxicities that we do worry about with bispecific antibodies and also seen in this regimen is the risk of infection, and particularly COVID 19 and pneumonia. Do you think that this will be a concern if this becomes a standard regimen and routine practice?
- [07:37]
C
I think you hit on a very important point, Lori. This is an important and emerging adverse event, not just with apqaritamab and not just in this trial, but I would say across the board with bispecifics. More than half of our patients have infections, particularly respiratory infections, and some of them being of grade three, grade four, including serious adverse events, and that was seen in our trial as well. So I think that it really deserves to be, you know, fleshed out. And my overall comment on that is that, yes, this is a profoundly immunosuppressive therapy. A little bit like CAR T cells, a little bit like other, you know, T cell engagers. They're certainly not just a B cell immunosuppression. I think it's a little more broad than that. And what that means in practical terms is that we really need to pay attention to how we can mitigate, prevent, and promptly treat these infections. And so things like VZV prophylaxis, things like PJP prophylaxis are certainly important components of the man of the supportive care plan for these patients. I used it in the clinical trial. I anticipate using it should this become an accepted and approved therapy. The use of intravenous immunoglobulins when there's recurrent infections or in patients that have really low levels of IgG 400 and below, I think is certainly something I have a low threshold for recommending with respect to the COVID portion. I think that, you know, this study being conducted really in the thick of the pandemic was really affected, I would say, quite significantly by cases of COVID including, unfortunately, severe cases of COVID I would not anticipate that being as large an issue going going forward, partly because of the herd immunity, partly because there's yearly vaccination, and partly because possibly the COVID infection itself has mitigated over the years. And I haven't really had, I would say, really substantial issues with interoccurring Covid in patients treated with bispecific antibodies, including clinical practice. So I think remain alert to it. There's ways to prevent, mitigate, and treat COVID infections. But I'm a little reassured that it's perhaps not as large an issue as it once was.
- [09:46]
B
In their commentary, Dr. Vitolo and Bonello suggested that, you know, in light of this very high efficacy, maybe the regimen can be shortened even more, and that might preempt some of these delayed infectious toxicities. What do you think about that?
- [10:02]
C
I think that's a great thought, and it's certainly not been lost on us. We've looked at a couple of different angles, and one is looking at patients in this particular trial who, for one reason or another, had to discontinue therapy in remission. Those patients did remain in remission for the most part, and that was, if you will, in trial, proof of concept that shortening treatment perhaps was not going to be detrimental. That idea was very much embraced and taken up in the recently completed Epcor FL1 study that looks at one year duration of therapy instead of two years of duration of therapy and that study was completed. The results will be presented very shortly at our ASH meeting and I'm very excited to share those results as well. So I think yes, that idea has a lot of merit. I think that if we were to redo this study today, we probably wouldn't do it two years. But understanding this is a population that includes heavily pretreated patients, I think a two year design was understandable at point this time.
- [11:01]
B
Great. Well, moving forward, I think we really look forward to seeing the results of that randomized phase three trial that's upcoming. In the meantime, I've really enjoyed our conversation today. Again, I've been joined by Dr. Lorenzo Falki who's been discussing the newly published article Fixed Duration of Caridamab plus R Squared Drives Favorable Outcomes in Relapse or Refractory Follicular Lymphoma and this is just recently become available on bloodjournal.org I'm also joined today by Dr. Robert Levy from the University of Miami. He's the senior author of a new Blood Journal article entitled Pre Transplant Targeting of TNFR SF25 and CD25 stimulates recipient Tregs in Target tissues, Ameliorating GVHD Post Stem Cell transplant thanks for joining us today.
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D
Thank you for having me.
- [11:58]
B
Perhaps you can start by giving us some background on the known pathophysiology of allotransplant related GVHD and in particular the role of Tregs.
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D
GVHD typically is initiated by conditioning the patient who's going to receive the transplant and that elicits damage, particularly in the gastrointestinal tract, which leads to the activation of antigen presenting cells. And those antigen presenting cells ultimately will stimulate the donor T cells that have been administered as part of the transplant, resulting in activating those donor T cells typically in lymphoid tissue. And after they differentiate, they leave the lymphoid tissues and move out into what we consider to be the major target tissues of graft versus host disease, which are the liver, the skin, the gastrointestinal tract, as well as some lymphoid tissues, including the thymus and bone marrow.
- [13:06]
B
So what led you to explore this approach of Targeting both TNFR SF25 and IL2?
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D
A number of years ago we learned that this molecule, TNF? RSF25, was expressed on regulatory T cells on Treg cells at reasonably high levels in contrast to conventional T cells, that is conventional CD4 T cells and CD8 T cells. And so several reagents were made by the late Eckhart Podak, which included a fusion protein made up of the natural ligand of TNFR SF25, namely TL1A, as well as a monoclonal antibody. And when using either of these reagents in vivo, we learned that we could really markedly expand the peripheral Treg compartment to levels that were five to six fold higher. And where they are physiologically now, T regulatory cells require IL2 or interleukin 2 to survive. And so what we learned in some earlier work is that if we expanded the T ray compartment to these high levels, they would quickly run out of IL2 and therefore perish. So we learned that if we could introduce some IL2 alongside of this reagent, we could keep the remarkably high levels of T regulatory cells. So that gave us the idea that, well, since we know when transplants are going to begin, we could manipulate these cells at the times that we wanted so they would be ready, so to speak, for when the transplant was performed.
- [14:57]
B
Can you summarize briefly your study methodology as well as your important findings?
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D
Sure. Essentially, we used this fusion protein that targets TNFRs of 25 in animals about three to four days, a little bit longer before the transplant was going to be performed, and also included Interleukin 2. So that led to a very large exposure, expansion of the regulatory cells in this mouse prior to the time where we gave them an allogeneic bone marrow transplant. What our thinking was that if we could expand these regulatory cells in this animal, and that they would persist after the animal received radiation and the transplant, they would be in place right away to basically prevent the large activation and expansion of donor T cells which leads to gvhd. In fact, what we found was just that. What was particularly interesting is that we looked in the target tissues where GVHD occurs, and we learned that T regulatories were expanded in those target tissues. Moreover, we learned that the expansion process actually was stimulating these Tregs that were already in the target tissues of the animal before the transplant in situ. In these tissues, they were undergoing proliferation. I think, importantly, when you stimulate through this TNF RSF25 receptor, the function of the T regulatory cell is also enhanced. What we basically set up was a regulatory environment in key target tissues that was ready for donor T cells. And what we saw is that the overall outcomes in terms of survival of the animals were very much prolonged. And clinically, when you look at the symptoms of graft versus host disease, there was clearly lower scores. And in addition, and this was very important, important because most of the allogeneic transplants are done for patients who have leukemia. We checked to see whether the anti leukemia responses were still intact in these animals in which we had dramatically reduced gvhd. And in fact they were. So the animals were able to mediate antitumor responses.
- [17:28]
B
So how do you think these findings might influence clinical practice in the future?
- [17:33]
D
That's a key question. So when we began this work a number of years ago, shortly after the year 2000, we really started working first, which was unusual, in trying to manipulate the T regulatory compartment in vivo. What occurred over the next decade or two is a lot of work utilizing the strategy of trying to isolate and expand Tregs in vitro and then transfer them into patients. And there's a lot of challenges with that because T regulatory cells can be expanded in vitro, but it requires significant effort and expense and so on. We've really always focused on the notion of manipulating them in vivo. And so what we thought was a good way that we could translate this into patients was basically to essentially treat the patient just immediately before the transplant. And we've made there are human reagents for stimulating both the TNF RSF25 receptor as well as the IL2 receptor. And we are doing work looking at responses of human Treg cells as well. So we think this is a potentially really good translational strategy. That's how we would go about implementing it.
- [19:05]
B
In their commentary, Harun Shaikh from the University of Wurzburg wrote that this might become a very important preventive strategy moving forward. But they questioned whether or not this could also be beneficial once GVHD has set in. What are your thoughts on that?
- [19:21]
D
I agree with that comment. I think where there's manipulating the T ray compartment in individuals, in patients who have GVHD has been reported by the group in Boston, John Korth and Jerry Ritz. And there was in fact some diminution of cutaneous graft versus host disease by treating patients who had chronic graft versus host disease. So one of the things I think that we've learned over time is that early after a transplant is performed, because of what's happening in the patient's immune system, it's really not possible to very effectively expand Tregs in individuals who receive the transplant. These are mice, of course, that we use. So a period of time has to go forward before whatever the environment is that supports it actually returns. So that was the reason that we thought we could start out with a pretreatment and get the regs in place before the transplant, with the potential then to utilize this strategy later on after a transplant if GVHD does emerge. And so I think ultimately that's probably a very good strategy. And we've actually begun, and I think we did include in the manuscript some studies where we're combining this strategy with other clinically used approaches for graft versus host disease. And so we think it can merge rather well with a number of these, as well as actually manipulating the compartment later on in a patient who has graft versus host disease.
- [21:05]
B
Great. I've certainly enjoyed this conversation today. I've been talking to Dr. Robert Levy, who's been discussing the newly published article Pre Transplant Targeting of TNFR SF25 and CD25 stimulates recipient Tregs in target tissues, ameliorating GVHD post HSCT. I think this important study demonstrates how preemptive approach of expanding host Tregs may lead to reduced GVHD and improved transplant outcomes, and this article is also now available on bloodjournal.org.
- [21:45]
A
Thank you for listening to this blood podcast of conversations with blood authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.