Introduction

DR LOVE: Good afternoon, everyone. I'm Neil Love from Research To Practice and welcome to “Practical Perspectives on the Current Role of Bispecific Antibodies in the Management of Non-Hodgkin Lymphoma.” This is part of our new “What Happened at ASH?” series. This is the third program we've done this week on this topic in terms of what happened at ASH.

We have a great faculty today, Professor Michael Dickinson from the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia. It's Thursday morning for Peter. I always like to, for Michael, I always like to think about Australians being in the next day in the future. And we also have Dr Laurie Sehn from the University of British Columbia in Vancouver, British Columbia in Canada.

Today we're here to talk about one of the most exciting developments in all of oncology, including hematologic oncology, which is the use of bispecific antibodies. Of course, we talked about that Monday night with our myeloma program as well. And today we'll be talking about some of the things that happened at ASH in this regard and kind of what they mean clinically.

As with pretty much all of our programs, we will be discussing the use of non-FDA approved agents and regimens so check out the package insert information for various products for more.

Both of our faculty are going to give presentations today summarizing some of the key datasets presented at ASH. Michael will be talking about papers related to aggressive lymphoma, diffuse large B-cell lymphoma. And Laurie will be talking about follicular lymphoma as well in terms of bispecifics. We're also going to bring up, we did actually one of our, we did 4 programs on the Friday CME thing that we've been doing forever now at ASH. We did a program, and actually Laurie I had met with her a couple months ago, and she presented some cases. And so we showed some of her cases at the meeting. I was going to give her some follow-up on what we heard from our faculty about her cases and see what Michael thinks about her cases as well. We have a couple other cases that we may get into as well.

But I just want to get into, here's where we're heading. We're going to talk a little bit about where things are heading in general, particularly as it relates to bispecifics, but also other products. And then we'll get into a couple cases. We'll get the presentation, more cases, presentation, back and forth.

Future Treatment of Non-Hodgkin Lymphoma (NHL)

DR LOVE: But to begin, just before we get started with ASH, I just wanted to take a deep breath and actually reflect back on what we heard the last couple days, because a lot of our audience has been online here the last 3 days. In addition to a lot of really interesting clinical datasets that came out at ASH, there were a couple things that we were talking about that really I thought were incredibly interesting, and I kind of want to ask our faculty whether they can come up with similarly interesting new developments and new agents in the management of follicular and diffuse large B-cell.

So Monday night, we heard about something I personally never heard of before, which is in vivo gene therapy, viral vectors that actually in vivo CAR-T therapy. So pretty much the off-the-shelf type therapy, which, kind of basically tries to simulate what happens with CAR T cells. It was really fascinating to hear about. And then last night, talking about ITP, this fascinating monoclonal antibody, ianalumab, which now has been used in second-line. There was a big Phase III trial that was presented. It's really interesting. It has 2 different targets, the BAFF-R pathway as well as ADC- mediated B-cell depletion.

So I just want to ask you two, do you have similarly exciting things? I've heard about a new bispecific out there with a CD19 target. But I'll start with you, Michael. First of all, do you have this in vivo CAR T in NHL? Is that something you're looking at? And what else is getting you excited that maybe the audience hasn't heard about?

PROF DICKINSON: Thanks, Neil. So yeah, I mean, I think that myeloma data was really exciting. To see those clinical responses was quite amazing. It's actually a complex field. There's a lot of in vivo CAR Ts being developed and certainly there are several trials in lymphoma. And I think that idea of reducing the practicalities of autologous CAR T is really exciting. I think it's too soon to know exactly where they'll fit in the paradigm, but I'm certainly looking forward to new data beyond myeloma and closer to my field.

I think the most promising class of drugs that we're seeing is the Bcl-6 degraders. This is the idea of degrading a particular target within the cell, in this case Bcl-6, with an orally available medication. And we saw some really exciting data from BMS in patients who were heavily pretreated with aggressive lymphomas, where this tablet taken twice a day can induce really clear-cut complete remissions. We need to see some more follow-up data from that, but that is a really exciting new class of drugs, I think, that opens up the way for treating these aggressive lymphomas beyond targeting the cell surface, which I think will be important as bispecifics become more embedded in standard treatments.

DR LOVE: So, Laurie, it's really amazing what general medical oncologists get exposed to in every single part of oncology. So much is going on. Anything you want to add to that? What about the CD19 bispecific? Can you talk about that? Also, there's an IMiD out there, or CELMoD, golcadomide. And any comments about this Bcl-6 degrader? We just got back from San Antonio. We were talking about selective estrogen receptor downregulators now maybe going to be adjuvant therapy. Any thoughts about this Bcl-6 degrader?

DR SEHN: Yeah, I would echo Michael's sentiments that I'm quite excited about the data that was shown at ASH. Several companies are now developing Bcl-6 degraders. It's fascinating because it's a novel target. It's one that hasn't been drugable before, and it's actually showing single-agent activity all by itself. It's a drug, to be honest, I would have thought would have to be combined to get the most benefit, and it is going forward in combinations, but the single-agent activity, I think, surpassed my expectations. So I think that shows a lot of promise.

Aside from that, I really think the ones you've highlighted are also intriguing because everybody's looking at what's next after CAR T and bispecifics, which really have revolutionized care for many non-Hodgkin lymphomas. And, golcadomide, we saw some updated data on that novel CELMoD, and it is looking really promising, particularly the single-agent data, but also in combination, and it may very well be a competitor or replace lenalidomide in the future or certainly is going to be building itself into multiple novel nonchemotherapy combinations.

And then, finally, the other bispecific antibody that's fair along in development, which is the CD19/CD3 directed bispecific from AstraZeneca, which is starting to show a lot of excellent single-agent activity. It's being taken forward in combination in various clinical trials and really serves to be another potential effective bispecific, maybe on the heels of the current ones not working or even replacing where we use the different bispecifics in the future. So a lot of really interesting data and a lot of promising options out there.

DR LOVE: So as we go along here today, I'm also interested in some of the ongoing Phase III trials, particularly ones that involve bispecifics and where these are and where maybe when we're going to see data even in the first-line setting.

Case: A man in his mid 60s with diffuse large B-cell lymphoma (DLBCL) and early relapse on axicabtagene ciloleucel receives glofitamab — Dr Sehn

DR LOVE: But first, just to get us in the mood of patient care before we dive into data, I want to just follow up about this case that we actually presented at the meeting. A patient of Laurie's, a 66-year-old man, diffuse large B-cell lymphoma, relapse, gets axi-cel, after 3 months has a partial response to axi-cel, but then at 6 months has progressive disease. And Laurie, you, at the time I spoke with you when we did this video, you had just started the patient on glofitamab. I'm curious if you have any follow-up of what happened. I guess that was a couple months ago. What happened with your patient?

DR SEHN: Yeah, so that patient is still receiving the glofitamab and currently doing very well. So it's still early days, but we do worry about those patients who relapse or don't respond, relapse early from CAR T or don't respond to CAR T because there is subgroup that may not get the same benefit from the bispecifics that we've seen potentially in other patients. But this patient despite the early relapse after CAR T is actually responding right now and still receiving the drug. So, it's early days, but I'm encouraged. The tolerance has been excellent and so far so good.

DR LOVE: And no major issues with the glofitamab in terms of tolerability? No CRS?

DR SEHN: No, nothing that was unexpected. So I think the tolerance of bispecifics on the heels of CAR T has been quite similar to patients who haven't received CAR T. So he tolerated both actually CAR T and bispecifics with just kind of low-grade toxicities. Sometimes we worry about cytopenias because patients post CAR T can have poor tolerance to other treatments, particularly if they are left with prolonged cytopenias. But his cell counts had recovered quite well and I would say that his tolerance to glofitamab right now has been very reasonable.

DR LOVE: So, Michael, kind of second opinion after what we heard at our CME meeting when we presented this case. One of the things that was, I think John Leonard, who was on the faculty, brought up was that this patient only had a PR on CAR T. And he brought up the idea of new strategies, new trials, looking at patients like that, maybe treating them at that point rather than waiting for them to progress. Any thoughts about that type of strategy? And the other point that came up here, and actually Laurie raised this question in the video, was what comes first, CAR T or bispecific? In diffuse large B cell, we've been hearing for a long time, everybody wants to go to CAR T first. Is that still the case as well?

PROF DICKINSON: Yeah, well, I mean, it's hard to say that I would do anything differently in a case such as this and the patient's outcome in some ways speaks for itself. But refractoriness to CAR T is a poor prognosis situation and it's clinically challenging and using conventional chemotherapies or drugs that could worsen cytopenias is a problem. And so I think that the bispecifics are really the default in that space at the moment.

And then, yes, there are a number of investigational trials being done in this space. We are doing a study looking at patients who have ctDNA positivity after CAR T cells where we're trying to come in early with the bispecific antibody because we've learned from the bispecific studies that having a lower burden of disease responds better to treatment. And so we're trying to capture the patients when they have a minimal burden of disease to prevent progression. That's exploratory at this time. I think we know that patients who have a partial response to CAR T can have an evolving response some of the time, but we like to see patients in a complete remission.

I think that CAR T at the moment is placed in certainly younger, fitter patients as a default second-line treatment because of the randomized studies showing a clear-cut progression-free survival and overall survival in that context, at least with axi-cel and liso-cel. And so in practice, CAR T is pretty firmly in that second-line space for most patients. But we know that access to CAR T is a problem and there are many patients for whom CAR T can't be delivered.

And I think that's the space where the exciting trials of bispecific antibodies also showing, in combination, also showing progression-free and overall survival advantage over standard chemotherapy, are very convincing. So we'll see some patients who get bispecifics first, at first relapse, and then for the younger, fitter patients where they have access, I think CAR T is fairly firmly placed in that paradigm in that space.

DR LOVE: So, Laurie, what's your current take in terms of eligibility for CAR T? We had another case presented of a patient who had some COPD, was actually on oxygen. The question came up, is that kind of an absolute contraindication for CAR T? How do you think it through? What's the oldest patient you've had go to CAR T, Laurie?

DR SEHN: I think it needs to be very individualized. There's no theoretical age limit for CAR T, but I think some patients, I would say, do have comorbidities or level of frailty that does make the risk of CAR T probably not worth the benefit, particularly if you have another option like a bispecific that could be better tolerated. So for the most part, I think we generally limit it to patients with an ECOG performance status of 0 to 2, prefer 0 to 1.

A patient with COPD on oxygen, I think if that has been a chronic condition and he's otherwise stable, I'd probably still refer him to my CAR T experts to weigh in on the risk-benefit ratio. But I think because many of these patients it is a potentially curative therapy, that we do give patients the benefit of the doubt, but it all depends on what your other options are. And I think there are undoubtedly patients that have other medical issues that prohibit them from going forward.

Case: A man in his late 60s with Type 2 diabetes, congestive heart failure and chronic obstructive pulmonary disease receives glofitamab monotherapy after glofitamab with gemcitabine/oxaliplatin for relapsed GCB-type double-hit DLBCL — Matthew Lunning, DO

DR LOVE: So, Michael, another case that was presented, this is from Dr Lunning, was a 68-year-old man, history of Type 2 diabetes, heart failure, COPD. Actually, I think this was the patient with COPD who was on oxygen, with relapsed disease, who initially got glofitamab/GemOx, had a difficult time with the GemOx, and then currently was on glofitamab relapsing, double hit, diffuse large B-cell. Any comments about the use of this combination and how people tolerate it? And any other comments about this scenario and this case, Michael?

PROF DICKINSON: Yeah, well, I mean, the choice of this treatment is based on the STARGLO study, which showed an overall survival advantage of the combination over GemOx monotherapy. So that's a really good choice. But the problem is that many patients don't tolerate Gem or platinum, sometimes due to prior therapies and sometimes due to comorbidities. And I think that's where some of the new combinations, where we've seen some new data, might be really quite promising alternatives, glofitamab in combination with polatuzumab vedotin or mosunetuzumab in combination with polatuzumab vedotin earlier in that treatment regimen.

So where this patient received glofitamab plus GemOx, if they were anticipated to be intolerant of that regimen, you might now reach for one of these new regimens, of course, approvals and availability allowing. But what's really interesting is this emerging theme that polatuzumab vedotin in the combinations could be quite effective for double-hit lymphoma. Because in some of the datasets of that combination, those patients seem to be doing a little better than expected, both of glofitamab monotherapy or of chemotherapy. And those patients were excluded from the STARGLO trial. So, actually, for a double-hit lymphoma patient who's relapsing, I think the pola combination data, which we'll be talking about a bit later on, is quite promising.

DR LOVE: Laurie, any thoughts?

DR SEHN: Yeah, I agree. I mean, I think the data on the glofit/GemOx looked really good, but the toxicity was there. The question is, do you come in in that scenario with a bispecific alone? Do you combine it with chemotherapy? Ideally, we're looking for chemotherapy-free options. But, sometimes we have patients with very high biology disease, they've got bulky disease, the bispecifics take a while to ramp up with the step-up dosing, and having a few cycles of chemotherapy in there may actually offer some benefit. But if I am going to use glofit/GemOx, I would consider, at what point maybe can you drop the GemOx if you elect to use it? And I do think that you don't need to continue it for the full 6 cycles, for example.

DR LOVE: That's exactly what Dr Lunning did, and the patient was doing really well.

Practical Perspectives on the Current Role of Bispecific Antibodies in the Management of Lymphoma — Prof Dickinson

DR LOVE: Okay, let's talk about what happened at ASH, particularly as it relates to bispecific antibodies in diffuse large B cell. Michael, take it away.

PROF DICKINSON: Thanks very much. So I'm going to be talking about bispecific antibodies, and you're familiar with the agenda for this talk. Here, I'm talking about CD3/CD20 bispecific antibodies, and as we've heard, there's some emerging alternatives, and some of the data updates looking at some of the established bispecific antibodies, both in combination and used in different treatment settings.

So the key things for me from ASH in this specific context was the updates on the registration data that led to the approval of bispecific antibodies in diffuse large B-cell lymphoma, some really interesting new combination treatments, and some updates from that data. And then, importantly, seeing these combinations move earlier into the treatment paradigm within the context of clinical trials. The epcoritamab monotherapy data was presented.

This is the updated data from the pivotal trial that led to epcoritamab approval. This was 157 patients, and you'll recall we now have there's really no change to the initial outcome data, which is that about 40% of patients experienced a complete remission to epcoritamab monotherapy. This was a mixed population of patients who'd received at least 2 prior lines of therapy. And the importance of this update is really about talking to patients about what can be expected from epcoritamab monotherapy with respect to durable response, and that question of whether bispecific antibodies can induce cures.

This curve shows the outcomes of patients who achieved a complete remission, and you can see that 46% of patients at the 4-year mark retained that complete remission. So when talking to patients who have that, we might say, look, there's roughly a 50% chance of losing that. I have patients who have been following up for a very long time from bispecific monotherapy trials, and they're now out at 6 and 7 years without relapse.

So I think there is a cure fraction from bispecific monotherapy, and we've seen that when we look at the glofitamab data and the epcoritamab data at the 3-year mark, they looked reasonably similar, but we're yet to see the 4-year data for glofitamab.

In combinations, we're seeing different strategies for combinations. Some combinations look to enhance the T-cell activity of these bispecific antibodies with co-stimulatory molecules, but there is also this orthogonal approach that we've alluded to in the prior discussion, taking drugs that target lymphoma through different mechanisms, trying to improve the outcome of bispecific monotherapy. We've seen combinations with chemotherapy, which we've touched on, but also with lenalidomide, the CELMoDs, which is an emerging class of agents, and then importantly, the antibody drug conjugates. These are all tractable combinations that we're going to see some data about.

The STARGLO study was updated at ASH. This is the study that randomized patients to receive either glofitamab with GemOx or R-GemOx in a randomized clinical trial, and it showed an overall survival advantage. And with further follow-up, now at 35 months, there's a persistent overall survival advantage, 25.5 months of median overall survival in the experimental arm versus 12.5 months in the standard arm. Importantly, we've seen that this difference between progression-free survival and overall survival has persisted with this long follow-up, so that's really important.

The authors looked at patients who'd received the trial either in the second-line or the third-line, because of that question around whether this regimen is a good one to apply in the second-line, and they saw no differences in this difference between the experimental arm and the control arm, whether a patient was in the trial in the second or the third-line, and that analysis was new at ASH.

We also saw some new data around the SUNMO trial. This is a study that randomized patients to receive mosunetuzumab together with polatuzumab vedotin, that orthogonal combination of bispecific antibodies and ADCs versus R-GemOx. This is an impressive study that showed a really striking progression-free survival advantage in the patients who received the novel combination. And what's striking about this combination is the very low cytokine release syndrome rate and the fact that it can be given as an outpatient regimen and the fact that it's been developed as a fixed-course regimen. So very exciting data.

We've seen some of that before when here the investigators looked at differences in quality of life and have shown that in the mosun/pola arm, by certain measures, there are clear improvements in quality of life as time goes on, quality of life being dependent both on the presence or absence of disease but also the toxicity of the regimen. And so we saw some updated data around that at ASH.

Glofitamab, which has a higher rate of CRS than mosunetuzumab but appears to induce a higher rate of complete remission and is perhaps a more potent bispecific antibody that's approved in diffuse large B-cell lymphoma, has also been combined with polatuzumab vedotin and that data was published in the Journal of Clinical Oncology recently.

What was updated at ASH and presented at ASH was this really interesting analysis of how patients with double-hit and triple-hit lymphoma or dark zone lymphoma performed in this combination. The authors deliberately enriched the study for patients with high-grade B-cell lymphoma and double-hit lymphoma so it's quite enriched for a study such as this with roughly 30% of patients falling into that category. We normally see about 10% of patients falling into that category in a trial such as this. And you can see really impressive progression-free survival that seems to be independent of that category and that I think is an important signal about the role of ADCs in this particular difficult subtype of lymphoma to treat.

Now moving to new combinations, we've touched on golcadomide, which is a CELMoD. Its mechanism of action is not hugely dissimilar to lenalidomide but it's significantly more potent. There's some monotherapy data that is active in diffuse large B-cell lymphoma. Now we're looking at a combination of golcadomide with either mosunetuzumab or glofitamab and with different doses of golcadomide evaluated. Here patients had received either a median of 3 prior lines for mosun or 2 prior lines for glofitamab and you can see the toxicities on the right-hand column are pretty consistent with what we see with both agents.

Neutropenia is an issue that is typically manageable and cytokine release syndrome that seems to be proportionate to bispecific monotherapy so no real surprises there in terms of toxicity. Activity appears promising noting that these are really small numbers, quite preliminary data, of patients treated at different doses but overall response rates and complete remission rates that seem significantly higher than bispecific monotherapy but we really need to see some expanded data before we understand how real that is. But again some further evidence that combinations might outperform monotherapy bispecifics.

Some of the most exciting data at ASH and over the last 12 months has been around moving bispecific antibodies into the front-line. There are currently functioning, currently run front-line studies looking at the addition of bispecific antibodies to chemotherapy with epcoritamab and glofitamab well advanced in that development and odronextamab also recruiting to trials there and those trials are randomizing patients to receive R-CHOP or R-pola-CHP. We know that that concept of combination of chemo plus bispecific is really tractable in the second-line and so we're looking forward to the results of those trials.

But in the meantime, there is some new emerging data. The data of odronextamab plus chemotherapy, the first part of the OLYMPIA-3 trial was presented at ASH. Relatively small numbers. No real surprises here. The regimen could be, the combination with CHOP chemotherapy was tractable. And here the authors presented the very preliminary data showing it's justifying the underpinnings of a randomized trial. And we're seeing nice durations of complete remission but quite small numbers here. I don't think we can take away too much from this except that the bispecific can be combined with chemotherapy and there's some justification for the randomized trial OLYMPIA-3 that they're progressing with.

Moving now to other ways of bringing bispecifics into the front-line. We want to reduce chemotherapy. Laurie touched on that. There are plenty of populations where it's difficult to give chemotherapy and if we're going to look at building a new regimen for diffuse large B-cell lymphoma in the front-line, we need to generate some data in these populations and there are several trials that have looked at bispecific antibody, monotherapy or combination as a first treatment in patients who are unfit to receive chemotherapy.

And this study of mosunetuzumab is one such study, quite inclusive, allowed double-hit lymphoma, allowed variants of diffuse large B-cell lymphoma. And this was a study for patients aged 80 or more or older than 65 with comorbidities that made them ineligible for chemotherapy. An ECOG performance status of up to 2 was allowed and patients received a fixed course of mosunetuzumab monotherapy. Forty-nine patients were recruited. The median age was 82.5. There was a good mix of patient characteristics, 71% of patients with advanced stage disease and importantly roughly 50% of patients with IPI 3 to 5 disease.

This is the outcome of mosunetuzumab monotherapy, a 73% overall response rate and a nearly 60% complete response rate and you can see now the early, and this is early data still, progression-free survival and overall survival showing that you can treat an aggressive lymphoma with bispecific monotherapy. It underperforms against chemotherapy for sure but there are populations where chemotherapy causes excess toxicity and this is really promising. The other really promising thing here is the low rate of cytokine release syndrome and the generally low grade of cytokine release syndrome with this monotherapy.

Epcoritamab monotherapy has also been explored in a similar population of patients, this with a longer follow-up, a median follow-up of 18.1 months. Again recruiting populations who are elderly, same median age of over 80, a good mix population. Here you can see the complete remission rate was analogous to mosun monotherapy and this gives us a little bit more follow-up than that trial and you can see that progression-free survival is perhaps unsatisfactory by itself. We want to do better than this but still promising that this will be an important building block for future regimens. Cytokine release syndrome is a little bit more common with this particular agent, which is not a surprise because we see that in the relapsed/refractory setting.

One of the really promising trials that was updated at ASH was this study from the German group looking at polatuzumab vedotin, glofitamab and rituximab as a first therapy in elderly and medically unfit patients. A fixed-course regimen just like glofitamab and polatuzumab, a fixed course, this was a fixed course and they recruited a cohort of 80 patients with a median age of about 80. They have defined them as medically unfit and frail and I think we're pretty satisfied that they recruited patients who were relatively frail here. The toxicity from this regimen was not a complete surprise. We saw significant rates of cytokine release syndrome but generally lower grade cytokine release syndrome, typically that's a first dose effect from glofitamab when it's used in this case. And you can see that in the right-hand panel here that the frequency of cytokine release syndrome decreases with treatment cycle. It's really a first dose effect.

But what's really quite striking here is the complete remission rate, 81% at the end of treatment and a progression-free survival with relatively short follow-up but decent numbers of patients being followed up at this data snapshot, a progression-free survival curve that looks substantially better with this combination than with the bispecific monotherapy studies I've just shown you, suggesting that that orthogonal combination could be applied as a chemo light, if you think of polatuzumab as light chemo in this patient population.

So I think, for me, the conclusions are that we're seeing durable remissions from bispecific monotherapy in the relapsed/refractory setting. STARGLO consistently shows the benefit of the novel combination over the standard chemotherapy with further follow-up, which is reassuring. SUNMO confirms what we know in the clinic that it's easier to give these drugs than combination chemotherapy. The Pola-Glo data, exciting with respect to high-risk lymphoma, single agents are active as a front-line therapy in chemotherapy ineligible patients, but this new combination looks really quite active and quite promising and suggests that we could move into other populations and reduce chemo in other populations perhaps in the future. So perhaps a window to the future. And then we've seen differences between these regimens in their toxicities. So I'll finish there. Thanks very much.

DR LOVE: Thanks so much, Michael. So, Laurie, Mohamed in the chat room wants to know how you select bispecific in diffuse large B-cell lymphoma. And I'm curious what your thoughts are about this R-pola/glofitamab combination. How are you usually approaching patients with comorbidities, older patients, et cetera.? Is this a strategy you'd like to use now? If you could, would you use it or can you? Have you used it?

DR SEHN: So maybe I'll tackle that question first. I have not used that combination. I still think it's very investigational. I agree it shows some promise. We're enthusiastic that with longer follow-up we will believe glofitamab is curative or has potential for cure. So why not move it forward? And there may be people that you can spare chemotherapy from. But I have to say, I think it's still very early data. That regimen is not without toxicity. The neuropathy was quite profound. The neutropenia was quite profound. So to say it's a chemo-free or chemo-light combination, it is not necessarily toxicity-light. Although I think the data is intriguing enough and I believe that they are trying to move that forward in a comparative trial. But personally, before I used it, I'd need to see more data.

And then the question regarding how to select which bispecific in aggressive B-cell lymphoma, I think, the ones that are approved right now, which is epcoritamab and glofitamab, in my mind, the efficacy data looks interchangeable. And so I think it's a matter of preference. As you know by design, glofitamab was given in a finite way and epcoritamab was initially as monotherapy been given to progression. Although, again, if these have curative potential, giving a bispecific to progression may not make sense. And I think there has to be some arbitrary cutoff used for those bispecifics that were intended to be given to progression. Because we do see mounting toxicity, particularly with infections over time. So I use both glofitamab and epcoritamab in my clinic, usually discussing the logistics with the patients and letting them choose.

Case: A woman in her mid 50s with multiregimen-recurrent follicular lymphoma (FL) receives mosunetuzumab — Carla Casulo, MD

DR LOVE: So we're going to move on now and talk about bispecific in follicular lymphoma. Laurie's going to do a presentation in terms of what happened at ASH. But again, a couple cases that we presented at our CME meeting. Michael, so this is certainly not an unusual case in that the patient, a 54-year-old woman with high, actually, high tumor burden FL, had previously gotten R-CHOP, progressed, got BR, progressed, got len/obin, progressed, got mosunetuzumab, having actually had a CR and doing really well.

One of the things that she brought up that we got into, and I'm curious in Australia how this works, is the interface between tertiary centers and community-based oncologists in terms of using bispecifics, both for diffuse large B-cell as well as follicular mosunetuzumab, for example. I'm curious how you approach it. A lot of times we see treatment getting started in an academic center and then the patient gets switched over. Do you see a day when the community-based oncologists are going to be starting bispecifics? How are you doing it right now in Australia?

PROF DICKINSON: So we have a public health care system and a private health care system in Australia. And the private health care system is probably the most analogous to the community-based oncologist system in the United States. And essentially there's been really rapid adoption of bispecifics when they've become available. And so when we're seeing that after people have understood the toxicities and understood the practicalities and treated 1 or 2 patients, then the comfort with the bispecifics has really opened up.

We are generally finding that we can deliver this to patients with very few admissions, even with glofitamab and epcoritamab. We're able to prevent admissions by risk stratifying the patients and then using corticosteroid prophylaxis in a way that seems to really reduce admissions. And so we're seeing these roll out quite comfortably, but I'm mindful that that's not the situation globally. But in Australia there's a lot of comfort about using the bispecifics. And I think some of that's because there's a lot of trial work done outside of the big academic centers as well.

And bispecifics have been evaluated in more common diseases like myeloma, even solid tumor trials. And so it's really the uplift of nursing staff skill that has opened this up to be treated outside of big academic centers. And just like treating febrile neutropenia, once you have it set up and people are comfortable with what they're seeing, it becomes much more easy.

DR LOVE: Laurie, any thoughts? And also, in our program on myeloma on Monday, we talked about a paper at ASH on myeloma and bispecifics using prophylactic tocilizumab. And I was just reflecting on the fact that I don't hear much about that with lymphoma, but myeloma, bispecifics, they're using prophylactic tocilizumab and a lot of the docs are very comfortable starting therapy. Any comments on that with bispecifics in lymphoma? And again, the interaction between the community and tertiary centers, Laurie?

DR SEHN: Yeah, I have to say I haven't seen that emerge as practice for lymphoma. I think the issue with the bispecifics for myeloma is that they do come with a higher risk of CRS. And so that has been by design to try and preempt that. I think that the rates of high-grade CRS are much lower in lymphoma. So probably that hasn't been emerging as a big initiative.

I have to say that particularly with the combination therapy and moving these bispecifics forward into treatment, the likelihood of having Grade 3 or higher CRS really is almost negligible. So we'll see some trials where most patients get just Grade 1 CRS, which I think is highly manageable. Many patients managed as outpatients. The Grade 2 CRS usually would prompt the use of tocilizumab, but that really is a minority of patients now with many of these combination trials. So I think it's a learning curve, but I think inevitably as these move forward into treatment, all oncologists, including community oncologists, will probably need to become comfortable and have a mechanism to manage patients right from cycle 1.

Case: A man in his late 70s with multiregimen-refractory FL receives mosunetuzumab with an ongoing complete response — Dr Sehn

DR LOVE: So Michael, one of my favorite — we showed, I feel like we've shown like a hundred videos in the last 3 weeks literally, between San Antonio and ASH, et cetera. But one of my favorites is this one with Laurie. I'll let her repeat what happened, because this is, again, another patient who did really well on mosunetuzumab, but a pretty striking situation. And the thing that really caught my attention, and I was going to ask Laurie to recapture what she said, was the feeling that I got when you saw this patient and the idea that you kind of like, wow, I think we're in a new era here. Can you talk a little bit about what happened with this man and kind of when you saw this happen, what it meant to you, Laurie?

DR SEHN: Yeah, so I remember this gentleman very well, because he was treated on our Phase I — it was part of the first in human trials for mosunetuzumab, so one of the probably first patients that was treated around the world. And he had already received 2 lines of chemoimmunotherapy and really had progressed through both of them and had a growing pleural effusion and no matter what we couldn't prove transformation. So it was all just really a stubborn, rapidly evolving follicular lymphoma.

And then he elected to go on this Phase I trial that we had, and within the first couple of doses that he received, which were still the basically step-up doses, he was already responding. And by cycle 2, everything was just disappearing. It was really quite remarkable. It was almost like a proof of principle of a new novel mechanism and drug that clearly was having a big impact for this patient. He was certainly my first patient that I think maybe one of the first patients I had treated with mosunetuzumab, but to see that profound response in somebody with such refractory disease was really remarkable.

And also, at this point, he is 78. He was not the fittest person, but fit enough to get on the trial. And his tolerance was fantastic. I mean, he asked me why I didn't give this to him before the chemotherapy. So I think we've gone on, obviously, to see how this has unfolded with the literature. And it really is a very impactful treatment for many patients.

DR LOVE: And Michael, I saw you nodding your head as Laurie was talking there. Another thing about this case that strikes me is we were talking about bispecifics in myeloma. A few years ago, we were doing a program where I was doing video interviews of patients. And I interviewed this patient who was on teclistamab, a monoclonal antibody bispecific, for myeloma. He'd been on it for 2 years, doing great, no side effects, great remission, et cetera. And the amazing thing was the day that I interviewed him was the day the drug was approved.

So a lot of our audience has only been in oncology less than 10 years. They don't realize that a while back, it wasn't that likely that you were going to benefit from being in a trial. Nowadays, a lot of people benefit. It's a Phase I study this man's still in remission from. Any global thoughts about where we've been and where we're heading, Michael?

PROF DICKINSON: The reason I was nodding was because Laurie was describing a situation that I had experienced too, treating patients in the Phase I study of a bispecific and these patients had highly refractory disease and you were seeing these responses often at quite low doses. And it really was one of those sort of wow moments. I remember running up to my one of my professional mentors and going, look at this scan! And we went, that's a real drug. And so that was a really exciting moment.

And I think the last decade in diffuse large B-cell lymphoma and follicular lymphoma have been really, really exciting with CAR T cells showing the impact of T-cell-directed therapy and then the bispecifics showing that you may be able to harness a similar mechanism with a drug is quite amazing. And then seeing that that can be done in a way that's tolerable for patients has been transformational. It's actually really shifted people's expectations. We were doing these trials that we just wouldn't see remission rates like this in Phase I studies. So that has been very exciting and I'm a little worried, of course, that maybe we might not see as much exciting coming through because the bar has really moved.

But it's very clear to me and I think all the data show that the bispecifics are bringing in a whole new era for B-cell lymphoma. So I would say before this 10 years it wasn't like that. It was all slightly improving this or that or changing the dose of rituximab or something like that and getting these incremental things. These big increments have been really exciting to be a part of.

DR LOVE: I think every oncology fellow has this sort of a, same kind of fantasy of the kind of experiences that you both just described.

FL and Other NHL Subtypes — Dr Sehn

DR LOVE: Alright, let's talk a little bit about what happened at ASH in terms of follicular lymphoma and other NHL subtypes specifically related to bispecifics. Laurie?

DR SEHN: Great, so I'm going to run through some of the abstracts that were presented and the theme here, spoiler alert, is generally bispecifics because for I don't know how many years now they've really been the highlight of ASH for follicular lymphoma, but they certainly were again this year. The first trial I'm going to mention is what's called the fixed-duration trial of mosunetuzumab. This is the trial that basically got the first bispecific antibody approval for follicular lymphoma. This was the pivotal trial done in patients who had received 2 or more prior lines of therapy.

And why I think it's important is because it's the longest follow-up we've seen to date. It is the 5-year follow-up. So most people are familiar with this data so I'm not going to give you the background, but mosunetuzumab is monotherapy. It was developed as a finite treatment. Patients got either 8 cycles if they were in CR or up to 17 cycles. But this is the 5-year data where you can see the median progression-free survival is 24 months. But that curve on the right, the time to next treatment, you can see that the median time to next treatment now is now known and it's 64 months. So people went on this treatment.

It was all done within generally 6 months or less for the majority of patients and yet they could have prolonged benefit here not needing another treatment on median for 5 years of time. So that really is quite remarkable, particularly this was a highly pretreated patient population that was quite refractory. Looking at those patients who achieved a complete response in this trial, the progression-free survival does show that many patients now out 5 years have had sustained progression-free interval. So, again, very encouraging.

We do see, of course, the curve coming down a little bit in follicular lymphoma. I don't think we're anticipating that this necessarily will be curative as it may be for DLBCL, but I think it's still short timing for follicular lymphoma to know whether or not that curve will level out at a plateau.

And importantly, this drug was developed to be given in a finite way, so we now have longer data. What happens on the heels of finishing treatment? Do you recover? Does the immune system recover? And what we're seeing is that the T cells remain generally unaffected. That's the curve on the right. The B cells plummet very, very low with this bispecific that targets B cells, but upon completion for those patients in CR, we do see those B cells coming back to normal, but it may take 12 to 24 months for most patients.

We also saw some longer-term data on another bispecific antibody, odronextamab. This is targeting the same CD20/CD3 targets. It's not yet approved in North America at this time. Their longest follow-up of 3 years also showed encouraging results. This bispecific antibody was developed to be given to progression, so these patients are receiving it for longer. Overall response rate 80%, CR rate 75%, very encouraging. And again, many patients having sustained benefit, but you can see the duration of response, duration of CR curves, they do come down over time. In terms of, here you can see the progression-free survival for all patients. Again, just the point that many patients can have sustained benefit.

What I did want to highlight about this agent is that one thing that does concern me for the bispecifics that are given to progression is that we are seeing a significant rate of Grade 3 or higher infections. Here, the Grade 3 or higher infection rate is about 45%, with 12% of patients having Grade 5 infections. I think that is really notable, and it's going to be my preference to make sure that these are probably given in a finite way. Fortunately, as they move forward in combination therapy, all the bispecific antibodies for follicular lymphoma are given in a finite way.

This abstract, I think, was probably the most important abstract presented at ASH. This was the Phase III trial called EPCORE FL-1, and it was the first trial to test a bispecific antibody combination in a Phase III setting. So this trial enrolled patients who had received only 1 or more prior lines of therapy, and it was a randomization to R-squared as per the AUGMENT trial versus epco/R-squared. So can we add the bispecific antibody into the R-squared background in patients who have received only 1 or more prior lines of therapy?

Looking at the characteristics of the trial, I'd say many patients were quite high risk in that they were highly refractory to prior therapy, a high rate of POD24 patients at around 45% of patients. In the trial, about 60 patients had had 1, 60% had had 1 prior line of therapy, and 40% had had more.

But this is the very impressive primary outcome curve, and that was that the addition of epcoritamab significantly improved progression-free survival, where we see the hazard ratio here is 0.21, and notably, it significantly improved the overall response rate and the CR rate. So really profound benefit.

In terms of safety, on the left, you can see what the CRS showed, and as I said before there was no Grade 3 or higher CRS, and the Grade 2 CRSs were very minimal and across the board very well tolerated, although there was an increased risk of neutropenia in infection compared with R-squared alone. So I think this will move forward as a potential new, very important standard of care.

Beyond this, the other abstracts I'll quickly run through really look at moving bispecifics forward into the front-line setting. We still don't have a Phase III trial yet here, but they're all being done. What we're seeing is Phase II data, various combinations. This was a look at using subcutaneous mosunetuzumab, which is coming out as monotherapy in patients in the front-line setting, and I would say just encouraging data here.

Here, the mosun is being given in the standard way up to 17 cycles, and patients could go on to get maintenance.

And, importantly, very high response rates here at 88%, high CR rate, and it was really quite well tolerated, but importantly, they did do ctDNA in a group of patients, and of those patients who were tested after only 4 cycles, 84% of them were MRD-negative.

And this is early days. The follow-up is only 22 months, but you can see here giving mosunetuzumab by itself in the front-line setting could lead to very high progression-free survivals. And it was actually very well tolerated in this patient cohort and in patients who went on to get the maintenance, which was just about half of the patients, even though it was given every 8 weeks at that point, there were no CRS events seen.

So this trial, I think, is interesting. This was a look at using mosunetuzumab in the front-line setting with lenalidomide but only bringing in the lenalidomide if necessary.

So we know that lenalidomide is used very commonly now in follicular lymphoma. Most of us don't like it. It doesn't make patients feel very well. They're being combined with the bispecifics in many of the ongoing combination trials, like the epco/R- squared trial I showed you. The question is, do you need the mosun? This trial started patients off who were previously untreated with follicular lymphoma, started them off with mosunetuzumab. They then went on to get tested. If their scans were negative, they just finished off with the mosunetuzumab. Otherwise, lenalidomide was added in. So it was an as-needed lenalidomide approach.

And what we saw here from this complicated curve is that they included both follicular lymphoma and marginal zone lymphoma, and only about a third of the patients needed to have the lenalidomide added in. All patients across the board, whether or not you're follicular or marginal zone, had a whoppingly high response rate, with CR rates over 80%.

And generally well-tolerated, but again, for the patients who didn't receive the lenalidomide, I would say that the safety profile was better. The safety with the lenalidomide was comparable to what we would expect, where we do see the fatigue, the extra neutropenia, and the rashes.

The one thing I'll point out here is that patients did, some patients had marginal zone lymphoma in this trial, and you can see the progression-free survival for the marginal zone lymphoma patients was actually better than the follicular. So we don't have bispecifics approved yet for marginal zone lymphoma, but I think this is very intriguing, and hopefully we'll see more studies exploring it.

This trial looked at the combination of epco/R-squared, like we saw in that Phase III trial, trying to move it forward.

I'm going to focus mainly on Arm 6 here. That was the group of patients who were previously untreated getting epco/R-squared, which now will likely be approved in the second-line setting based on that Phase III trial.

But what happens if you give epco/R-squared in the front-line setting? Well very impressively here, the overall response rate was 95%, CR rate almost 90%, and that curve, still with 3-year follow-up almost, is very flat and very high for progression-free survival above 90% and 100% of patients having MRD negativity and very well tolerated with no unexpected toxicities.

Just in closing minutes here, this combination I thought was interesting, mosunetuzumab and zanubrutinib. It's investigational.

It was looked at as a combination in this group of patients with front-line follicular lymphoma given both over 12 months.

And just the punchline, very high overall response rates, over 90%, high CR rates, about 80%, but median follow-up of 6 months, just very short and no unexpected toxicity. So we are intrigued about zanubrutinib because it is approved now in combination with obinutuzumab for follicular, but this combination of bispecific and zanubrutinib, I think, is intriguing, but we need more data.

At this slide, I'll just mention this briefly. So odronextamab we saw in DLBCL is being investigated in combination for chemotherapy as similarly in follicular lymphoma.

This was just the lead-in to the Phase III OLYMPIA-2 study being done in follicular lymphoma as well. I'm not very enthusiastic about this because I think our goal is to get rid of chemotherapy up-front in follicular lymphoma. Here we saw high response rates, but again, I'm going to highlight very high rates of infection, which I think is a problem when you add the bispecific odronextamab to the chemotherapy. So, early data. This will move into a Phase III and compare itself against chemoimmunotherapy alone, but I'm not very enthusiastic based on it keeps the chemotherapy in the front-line setting and the high rates of infection.

And then finally, we have talked mainly about where the bispecifics are going. We've got epco/R-squared now approved in the second-line setting shortly probably based on that Phase III trial. I'll just highlight the next Phase III trial that we expect to read out, and this is the combination of mosun/len also being tested in second-line patients and beyond. We saw some early data from this trial. This was the nonrandomized cohort that was done in the US to extend the patient numbers, and I think it may just be foreshadowing to what we expect to see at the summer meetings when the Celestimo Phase III trial reads out and that that is also a very effective combination with high response rates and durable benefit.

Finally, bispecifics are also being evaluated in mantle cell lymphoma. This, I think, was an innovative combination of the glofitamab, lenalidomide and venetoclax combination. It is a Phase II study.

So small number of patients, but in this group of patients in the front-line setting, they picked out a very high-risk cohort.

And with kind of a bit of a complicated regimen where they introduced the agents sequentially, but ultimately giving all 3 agents simultaneously, they saw very high response rates and very high level of MRD with over 96% of patients becoming MRD undetectable and that very impressive progression-free survival curve on the right.

So more data just showing how bispecifics are effective, particularly for follicular lymphoma, but intriguing results there for marginal zone lymphoma. We know the data is evolving for mantle cell lymphoma and the theme is that it's moving forward.

DR LOVE: So really awesome, very interesting. One final question back to you, Michael. Where do you see bispecifics heading in terms of mantle cell? We were just talking about this.

PROF DICKINSON: Well, we have some data from glofitamab monotherapy and there is currently a randomized trial running globally to compare that against conventional chemotherapy in patients with 2 prior lines. In this particular setting, there is a little bit of a signal that there's a little bit more toxicity from the bispecifics. So that's an important point. The other issue is that the CR rate is terrific, like really looks comparable to CAR T. So that's kind of important.

Durability data is a little less impressive, partly confounded by COVID-19 when that trial was run, when that Phase II trial was run that led to the Phase III. But I use glofitamab in practice in trials and have seen some really impressive responses in patients who are progressing with poor molecular features. So, anecdotally, I think it will find a place so long as we can manage that toxicity.

I agree with Laurie's point around follicular lymphoma about the curative fraction being unknown. And I think that applies to mantle cell lymphoma as well. So I feel like the paradigms for the use of bispecifics in these indolent lymphomas might be a little bit different in terms of relapse rate after fixed-course therapy. So, but I think it's very promising and there are a lot of investigational trials going on in that space at this time.

DR LOVE: So, Laurie and Michael, thank you so much for joining us today. Audience, be safe, stay well and have a great night. Thanks so much, Laurie. Thanks so much, Michael. Have a great one.

PROF DICKINSON: Absolute pleasure.

DR SEHN: Great, my pleasure. Thank you.