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Dr. Jeremy Abramson:
Welcome to The ASCO Post Roundtable Series on Clinical Advances in Diffuse Large B-Cell Lymphoma. I'm Jeremy Abramson from Mass General Hospital and Harvard Medical School in Boston, and joining me today are two of my wonderful friends and colleagues, Drs. Laurie Sehn and Kieron Dunleavy, who will introduce themselves.
Dr. Laurie Sehn:
Hi, I'm Laurie Sehn from BC Cancer and the University of British Columbia here in Vancouver, Canada.
Dr. Kieron Dunleavy :
I'm Kieron Dunleavy from MedStar Georgetown University Hospital and Georgetown University in Washington DC.
Thank you both for joining us, and thanks to all the viewers. Today, we'll be discussing recent updates in the treatment of diffuse large B-cell lymphoma, and integrating these new developments into three patient scenarios in DLBCL management. Our last installment here will focus on third-line and later treatment for relapsed/refractory DLBCL.
And we'll return, of course, to a case, and our case is patient LE, who was most recently treated with axicabtagene ciloleucel as second-line treatment for diffuse large B-cell lymphoma, non–germinal center subtype, which relapsed 11 months after pola-R-CHP.
With treatment with axi-cel, she developed grade 2 cytokine-release syndrome on day 2 and received tocilizumab, with rapid resolution of symptoms. She developed confusion on day 4, consistent with grade 2 ICANS, or immune effector cell–associated neurologic syndrome, for which she received dexamethasone, with improvement of that toxicity over 7 days. At day 30 after axi-cel infusion, she's found to have a very good partial response on PET-CT, and is now recovered from toxicities. But at day 60, unfortunately, she again has progressive disease.
So when we turn to Dr. Sehn and say, Laurie, what would be your option now for third-line treatment in this patient relapsing, now 2 months after axi-cel?
So this is definitely a challenge. I think what we have to do is examine what our goals of therapy are in this patient, and the treatment here probably is going to need to be tailored to the patient. In general, we would think that, do we have any further curative therapy to offer her? I'd say this is a challenging scenario where we don't know that any of the further treatments we have are truly going to be curative. So I think it becomes a balance of, what are the options that we have, weighing them with the toxicity of those options. The goal here would still be to try and get durable disease control, and hope that we can relieve symptoms and prolong progression-free survival.
What's amazing is that there have been a multitude of new therapies available for this setting now that we didn't have previously. So historically, we used to use chemo or chemo-immunotherapy, again, trying to resurrect some value out of chemotherapy. And the one thing I can honestly say is I would rarely use chemotherapy in this setting anymore. So I think we've all moved onto novel therapies. What are our choices? Well, our choices have included the novel therapy combinations, including polatuzumab with BR, we have tafasitamab-lenalidomide, we've got loncastuximab tesirine, and we've got selinexor, and more recently now, we have bispecific antibodies. So I'm throwing that out as the potpourri of options that we now have. I think based on the weight of the data from all of those options, and we can dig into the details, but I would be trying to get this patient a bispecific antibody.
Kieron, how about you?
Dr. Dunleavy :
Yeah, I would totally agree with all that Laurie has said. I think when it comes to third-line therapy and beyond, you really do need personalized medicine, because the toxicities from prior treatments, the ability of a lot of patients to endure X therapy, et cetera, can become a big issue. So there are a lot of different factors to consider. I would totally agree, I think that based on recent data, the bispecific antibodies, which target CD20 on B cells and CD3 on T cells, look very promising for patients with relapsed and refractory DLBCL. In the U.S., we have two that are approved, glofitamab and epcoritamab, and if you look at the outcome for patients with relapsed DLBCL, and there now are several publications looking at this, the remissions are sustained for a long period of time.
And if you look at those people who achieve CR with either of those two bispecifics, a huge proportion of them remain in CR with pretty long follow-up, so they do appear like a very promising strategy for third-line DLBCL. But of course, over time, we will have longer follow-up with them. And I think with these patients with DLBCL, we're always trying to cure them. So in the third-line setting, our goal is typically to still cure. But we don't know if the bispecifics are curative in the third line, but we do have data showing that people remain in remission for a long time, the follow-up that has been done. But over time, we will get a deeper picture of their effectiveness in the setting.
I agree completely. I would also be looking to get this patient to a bispecific antibody. It's really quite remarkable that only within what seems like the last few weeks, we suddenly, in the United States, have two FDA-approved bispecific antibodies in exactly this indication, glofitamab or epcoritamab, both, as Kieron points out, target CD20 with a tumor binding antigen, and bind CD3 on the patient's autologous T-cells to bring them in to exert cell-mediated cytotoxicity. And both products induced complete responses in about 40% of patients, and what's perhaps most remarkable is that the response rate does not appear to be significantly different based on whether a patient had received a prior CAR T-cell. And so, I think we do have reasonable data from the pivotal trials that these are good options for patients relapsing in the post CAR T-cell setting, which previously, I would say, has been a fairly poorly met medical need.
Now, Kieron, it's always a challenge when you suddenly have two drugs available with a similar mechanism of action, but there are differences between glofitamab and epcoritamab, and I wonder if you could compare and contrast them a bit, just thinking about how you're going to approach that discussion with your patients.
Dr. Dunleavy :
So I think it's really difficult, because, obviously, these bispecifics have been studied in single arm studies, so they've not been compared to each other in terms of their toxicity or their efficacy in DLBCL. In terms of choosing glofitamab or epcoritamab, as you've said Jeremy, it's all very, very new to us. I'm just at the moment trying to get epcoritamab for one of my patients, and it's a challenge. In terms of selecting one over the other, epcoritamab is administered subcutaneously and glofitamab intravenously. Logistically, obviously, that is very, very different in terms of long-term therapy, and these therapies go on for a long duration. Another big difference is that the way glofitamab was studied in relapsed DLBCL, it's time limited therapy, essentially, it's given for 12 cycles, whereas epcoritamab is given indefinitely until disease progression. Those are two major differences.
There are toxicity differences in the published studies, but it's really difficult to compare, I think, and contrast these agents when they haven't been actually compared with each other in a study. We can compare the studies but they were done differently. So that's how I would think about it. But they both are highly effective, from the publications, in DLBCL, so I would highly consider them for somebody who has relapsed after CAR T-cells. And as you said Jeremy, they do very well in patients who are refractory to CAR T-cells, in that subset of patients, which you would think are really, really refractory patients, they have had good success in that subgroup.
And Kieron, as you pointed out, one thing that's most impressive is, in the glofitamab data, which is time limited treatment, how the majority of the complete responders have remained in remission, even being off therapy for 6 months, 9 months. And so, it's tantalizing to think that perhaps some of these patients are cured, although, I think with the 12 to 18 months of median follow-up that we presently have, it's a little premature to claim that, and I think we're going to need longer term follow-up to know if these bispecific antibodies are curing patients, which I think we're now quite convinced that CAR T-cells are. Which begs the question, Laurie, if you've got a patient in the third-line setting who's received just conventional therapy to date, they've not received a CAR T-cell, and they come and say, "Dr. Sehn, I've heard about these dramatic advances in immunotherapy, do you think I should get a CAR T-cell or a bispecific antibody as my third-line therapy?"
So right now, with the weight of the information we have, I think it's fair to say that we've got solid data to say that CAR T-cell therapy offers curative potential, and we just don't have the long-term data for bispecifics yet to make that strong claim. So if a patient was suitable for both, because I think there are some toxicity differences, there will be patients for sure where we feel, due to frailty or multiple comorbidities, they're not CAR T-cell candidates, but many of them will be bispecific candidates because the toxicity profile is lower, and I think that's fair to say. But a patient who is eligible for both, at this point in time, I would have to advise them that CAR T-cell therapy would be considered the standard of care over a bispecific, just because we don't have long enough data.
That'd certainly be my approach as well. I also think it's striking, we're all at large academic centers, we're fortunate to have access to all of these treatments, there are a lot of places, in the United States, and Canada, and elsewhere in the world, where accessing a CAR T-cell for a patient might be very difficult, require extensive travel, require financial resources they might not have. I think an elephant in the room is needing to bring these treatments closer to where patients actually live so that more patients can access this lifesaving therapy. But one of the great appeals of bispecifics is they should be more broadly available, they're off the shelf products. And so, also for those patients who just aren't able to access a CAR T-cell, how wonderful now to have this additional active immunotherapy and bispecifics available for those patients.
And Kieron, we've gotten, I think, so spoiled by having CAR T-cells, and having suddenly bispecifics now available, but Laurie earlier went through this panoply of other options potentially available, polatuzumab-BR, tafasitamab-lenalidomide, loncastuximab tesirine, selinexor. How do you think, in a patient who's exhausted these immunotherapy options, and you're going back to these slightly more conventional therapies, although recognizing those are all modern advances over historic chemotherapy, how are you thinking about personalizing care using tafasitamab, polatuzumab, loncastuximab, et cetera?
Dr. Dunleavy :
Yeah, so I think in the context of the patient that we've just discussed, one thing is that she's just had an anti-CD19 therapy. So what is the potential benefit of giving further anti-CD19–directed treatment? So if she gets, for example, tafasitamab with len, or loncastuximab, is likely to be helpful for her, considering she has progressed after CAR T-cells that target CD19. There are some patients who will respond to those anti-CD19 treatments, even after getting anti-CD19 CAR T-cells, but the proportion of patients is not huge. So I might want to think about targeting something else other than CD19 in a patient like this who has progressed after CAR T-cells. Having said that though, there aren't a lot of good options, and one challenge with this group of patients is that they tend to often have low blood counts, and certainly when they get chemotherapy, their threshold for developing cytopenias is very, very low. So it is attractive to think about non-cytotoxic treatments in this group of patients.
Yeah, I agree entirely. I'm often thinking about polatuzumab, if they haven't already had pola, often omitting the bendamustine, because as you point out, these patients are often cytopenic after all their prior treatments. If I am thinking about a CD19-directed therapy, I typically will do a biopsy to see if CD19 is still expressed, and loncastuximab, which uses a completely different toxin, a pyrrolobenzodiazepine dimer, as opposed to a MMAE on polatuzumab, is a novel therapeutic if they still have CD19, and in the LOTIS-2 trial, there were responses, even in heavily pretreated patients. Although, with loncastuximab tesirine I will caution, it does have a unique edema-like syndrome that warrants pre-medication with dexamethasone for 3 days, beginning the day before loncastuximab tesirine dosing. So these agents are indeed available, and tafasitamab-lenalidomide, again, thinking in a non-GCB patient where maybe lenalidomide would have added benefit.
And then, I suppose there are some niche subset of patients. We haven't talked a lot about primary mediastinal B-cell lymphoma, but an immune checkpoint inhibitor, a PD-1 inhibitor, would be a wonderful consideration in a patient like that. A non-GCB patient, particularly if we knew that they had MYD88 and CD79B mutations, next-gen sequencing would be an ideal candidate for ibrutinib. And so, I think when we get into the post-immunotherapy setting, really, treatment needs to be personalized to the patient.
But I think there's no question, thinking about this panoply of options available, as well as the improved options in first line and second line, it's really remarkable the advances of how far we've come and what a great debate that we can have amongst us on how to incorporate these newer, highly targeted, highly effective drugs, for the benefit of our patients.
Dr. Dunleavy :
I think in a patient like this, we've made huge progress as well in our understanding of diffuse large B-cell lymphoma biology, and have identified a number of mutations and a number of subtypes of the disease, that these are patients that we should highly consider for clinical trials, because there are a lot of very interesting agents that target specific subtypes of DLBCL. And I think for us to be sitting around having a similar discussion in a few years’ time and talking about new agents and new discoveries, we need to do that, we need to refer our patients to clinical studies, and at third line, patients who had CAR T-cells, I think, is a good candidate for this.
I would absolutely echo that. Despite the great progress we've made and the multitude of options we now have, there will still be patients that need the development of novel therapies. And most importantly, one of the most critical unmet needs is really understanding the biology and the predictive markers that we might be able to use, to be able to select, or to optimize, therapy for individual patients. So I think we still have a lot to learn, and clinical trials really should be considered strongly for patients in this setting.
Well, I can't imagine better parting words than those comments from Kieron and Laurie, also highlighting the need that the three of us are going to need to get back together in this forum in a couple of years and revisit these advances with those that are following on their heels.
But for clinical takeaways for this third case, I'll remind everyone that for third-line and later management of diffuse large B-cell lymphoma, CAR T-cells are preferred for most patients, if they've not previously had CAR T-cell therapy in the second line, and that includes axi-cel, liso-cel, or tisa-cel, as third-line or later treatment. For patients progressing post–CAR T-cell therapy, or without access to CAR T-cells, the anti-CD20, CD3, bispecific monoclonal antibodies, with the approved versions being glofitamab and epcoritamab, are now approved, and preferred treatment options in the post–CAR T-cell setting, or non–CAR T-cell setting, in the third-line or later population with high rates of durable response. And in the post-CAR, post-bispecific setting, options will be personalized to the patient based on their prior therapy, comorbidities, and tumor characteristics. And options there will include tafasitamab-lenalidomide, polatuzumab-BR, loncastuximab tesirine, and chemo-immunotherapy.
And so, that brings us to the end of this case. Please see the other segments for further discussion about the latest data in diffuse large B-cell lymphoma, or visit ASCOpost.com.