Hello, my name is Marion Subklewe, and I’m greeting you from Barcelona where currently we have the iwNHL meeting. And we just had a really interesting session on bispecifics in lymphoma, and we’re going to talk and continue our discussions. And I’m really happy to have introduced to you the faculty that has joined me. So we have Loretta Nastoupil from MD Anderson has joined me. Um, and we also have, um, Rajat Bannerji from New Jersey, Rutgers university. And also joining me as a co chair is Carmelo Carlo Stella from Milano. So, um, all welcome. Thank you. Um, it’s great to be here, and I will start with giving you a short summary of the talks that were just presented. So I hand over the world of Loretta.

So we’re covering by specifics, which I think is really an interesting, um, an exciting development for the treatment of B cell lymphoma. So I covered mosunetuzumab which is a CD20xCD3 bispecific. It has some features that I find intriguing, particularly the safety profile. So we see very low rates of grade two or higher CRS most or by far grade one. Most occurred during the first cycle, uh, and it has fixed duration doses, which I think is also intriguing for patients. And so I covered was the Phase II single-arm study of mosunetuzumab in relapsed refractory follicular lymphoma. About 90 patients that were pretty heavily pretreated. So median of three prior lines of therapy. Uh, the primary endpoint was complete response rate, which was 60% which again was quite intriguing for this patient population. It’s eight cycles of therapy for the vast majority of patients. And then I covered some information that was updated this summer with retreatment, which suggests that can be a successful strategy when patients relapse, safety profile and itself. Well, the combination strategy. So I’m pretty excited about where we go next with most of those.

Um, yeah, I think the safety profile is really intriguing, and I think you also show data of first line elderly patients. Maybe you can further comment because I think it also just underlines the safety profile that was seen.

Absolutely. I think, you know, in follicular lymphoma, we have so many options. And so if you have a new therapy that’s available, it needs to be safe. It needs to be well tolerated, and it has to have efficacy. I think we can see that with follicular lymphoma. To be critical in the aggressive histologies we don’t see some of the efficacy rates that my colleagues will share with you with the other agents. But because the safety profile is so intriguing and you do see a little tail to that curve, there is a subset of patients that have really durable remission. To me, it makes perfect sense to try this in elderly or unfit frail patients that are not appropriate for anthracycline-based therapy as early as frontline because their options or their outcomes are so dismal when they can’t have standard of care options. And so there was a Phase I study in small number of patients, but quite intriguing, very well tolerated. We do see some durable responses in a subgroup of patients. I think it would be an attractive option for those patients.

All right, so before we then go on further with the discussion, I give the word over to the next bispecific.

Right, so I’m Rajat Bannerji of energy from New Jersey. And I spoke about odronextamab, a CD20 by CD3 bispecific from the company Regeneron. And we’ve been involved with that first in human study, uh, dose escalation study from, uh, from the beginning. And I presented data on that study with a little bit of, uh, a little bit of a focus on CAR-T failures in large cell population. So, uh, for this study, we saw a response rate of 53% in diffuse large B cell lymphoma patients who had not had prior CAR-T therapy and, uh, small numbers. But all those were complete remissions. They seem durable. Uh, and then we looked at patients who had had prior CAR-T therapy large cell lymphoma patients. Uh, the overall response rate was 30% and the complete response rate was 27% again in about small numbers. And there were 30 patients, uh, 10 responders, eight CRs, and those seemed durable. Uh, and then I reviewed with the audience, um, some additional translational data looking at what happens in two patients who were CAR-T failures regarding the residual CAR T cell population and, uh, and the remaining endogenous T cells. And at least in the data that was presented, it seemed that the endogenous T cell population proliferated. Um, whereas the car t population that was there did not, um, suggesting that the endogenous T cell population is responsible for the response in those two particular patients. The CAR T target CD19 was still present on the tumor cells despite prior CAR-T therapy. Um, and so again, very indirectly that may suggest that the bispecifics, at least in some patients, are overcoming mechanisms of resistance that have to do with, uh, loss of T cell activity. So that was kind of my focus today. Thank you.

You can ask already one question. So there are all these different bispecifics evolving. Lots of them targeting CD20 currently, at least in the lymphoma setting. Um, what makes the different constructs unique? And what do we know about antibody format and possibly efficacy? Is there anything known about it or can you comment?

Yeah, I can. I mean, I can comment a little bit on the structure of the antibodies. I think the harder question is really what’s driving efficacy and is, um, you know what was in quotes advertised as the benefits of each antibody based on their construct. Is that really what we’re seeing biologically in the patient? That I don’t know. Um, but in terms of the four antibodies in development. Odronextamab is the only one that’s using a full IgG4 backbone. The other three are using IgG1, Um, because these are full immunoglobulins. Uh, the half lives are much longer than, um, at least in the US, the only FDA approved bispecific, uh, blinatumomab, blincyto, which is a small peptide, um, and has a very short half life. So these allow for intermittent dozing, and all of the, uh, drugs that we talked about are dosed once a week once every two weeks, once every three weeks, depending on which product it is. Uh, And then we have some unique features. We’ll hear about glofitamab shortly, but it has this two-to-one design. So it binds the target CD20 antigen at two sites on the, uh on the antibody construct and CD3 on one site. Um, the other three constructs, uh, have a standard uh, have 1 to 1, uh, construct and, uh and I think I can’t think of any other structural changes between them. Um uh, and the only other thing I would point out is is one of them, uh, epcoritamab, uh, development plan has been subcutaneous from day one. Um, the other three products are sort of catching up in that space as well, but I think we’ll hear a little bit more about that,right.

So we can say pharmacokinetics are influenced through, um, through the format.  Right. Um, we have this one exception glofitamab, um, so that’s going to be next through the bidle and bending and increased avidity. And the other part is probably unclear how it impacts safety or efficacy. Is that correct?

The other parts of the structure, it’s It’s unclear. Um, although, you know, again, uh, we saw a little bit more early CRS with our, uh, with our next amount of the drug that I worked on, but I don’t think that’s, uh, clearly related to the structure of the agent. I think the pharmacokinetics have been published for all of them, and they, uh, seem, uh, initially, uh, to be cleared by binding to target and again, uh, and then, uh, once that saturated seems quite predictable.

All right, so now we’ve already talked a little bit about glofitamab, and I had over the word to you to share some of the data.

Thank you Marion. I covered the results of glofitamab with a specific focus on the pivotal Phase II expansion court, which represents the backbone for registration application Roche has filed to the EMA uh, in terms of, uh, configuration as this peculiar to to one ratio with two, uh, antigen binding site for CD20 and one for CD3. And this is one, uh, is probably related to the higher potency of activity that this antibody has as compared to the other bispecifics. The other point is that glofitamab has a FC receptor, which is associated with a longer, uh, life of the of the molecule. One third characteristics that is probably related to the molecular configuration is the fast activity that this, uh, antibody is all patients we have been treating during the phase one. But also particularly in phase to achieve the optimal and the maximum response after cycle two, just before receiving cycle three. Uh, so this is one feature intrinsic to the region that has to be, uh, to be kept in mind, uh, in the face, when we plan additional studies or additional treatment scheme with this, uh, molecule. And these are positive, uh, features because, particularly in patients requiring a fast debulking, you can use this molecule appropriately. Now, in terms of the in terms of results, what is emerging? The Phase II pivotal expansion cohort enrolled more than, uh, 145 patients. Uh, and these were all patients with diffuse large B cell lymphoma with, uh, high risk characteristics in terms of patients that had been prior highly pretreated. Uh, they had received at least two lines of chemotherapy, but the median number of prior chemotherapy was free. So really patients, uh, with high, long history of chemotherapy, and they were also really refractory because, uh, the primary refractory patients in this, uh cohort was around 60%. Another feature of high risk was represented by the evidence that the 33% of those patients have been treated with CAR-T and and failed this procedure. And now, uh, today patients who failed CAR-T really represented the worst unmet medical need in the field of diffuse large B cell lymphoma. So this is a particular relevance of this population, despite this, uh, therapeutic glofitamab resulted in a 39% complete remission rate, which is higher than the fixed endpoints. So the study drug met the primary endpoint. Uh, and, uh, in addition, uh, sticking to the efficacy results. What is surprising with glofitamab specifically in this patient population of highly treated and highly refractory patients is the duration of complete response. Because for 40% of those patients achieve a complete response, and, uh, with a follow up of one year, uh, a very high percentage of them still remain in a complete response. These percentages around more than 60 more than 60%. Uh, so this means that the drug not only is very effective, but there is, uh, the patients treated with this drug experience experience, uh, substantial durability of response. And, uh, as you know, uh, the LBCL patients who remain in a response after one year and particularly after 24 months,  uh, can be considered, uh, longterm responding patients and the candidate potentially to a curative response, which is very important in this specific field. Uh, in terms of safety, uh, the current treatment plan of schedule of administration used with glofitamab which is based on a step up dosing, uh, seems to be very safe with a minority of patients experiencing cytokine release syndrome of grade three. No more than 22.5%. Whereas, uh, the other CRS when they appear, uh, grade one or grade two making the drug, uh suitable for an outpatient, uh, use, uh, when will be approved and would be also on a large scale. Uh, setting.

Yeah. So maybe a few last words to safety. I think, and please correct me, that it also has to be differentiated in which disease setting we are actually using the bispecifics. Right. So there is less toxicity in the follicular lymphoma setting compared to the large B cell lymphoma setting where in general toxicity was a bit higher. And actually that compare also to the CAR T cells, where we see higher toxicity in the large B cell lymphoma compared to follicular lymphoma, where we also have a much safer profile. And let’s see yes and also ICANS. Do you agree, or can you comment?

Yes, absolutely. Let me add the only one point that B cell lymphoma require a specific attention because, uh, they may have disease sites or disease extension, which is substantially different as compared to for follicular lymphoma. So we need, uh, to be well trained when using this this drug, and we need a learning curve and appropriate learning curve just to recognize on a very early phase the potential risk inherent to treating patient with the specific disease localization, for example, mediastinal or uh, bulky disease or gastrointestinal localization. This require a specific, uh, capacity of recognition and regards also to, uh, prevent a potential, uh, side effects. But it’s part of our job, and the experience of a party in this respect is really very important. Yeah, and I think the safety aspect is really important. If we think of combinatorial approach is, and maybe we’ll talk about that last time. So I’ve just questions to also response and and all the novel tools, T Cell based immunotherapy that are now available. So maybe each of you can comment where you see the bispecifics and we have to talk about the elephant in the room, the CAR T cells. If you look from the bispecific perspective to this.

So where do you see in follicular lymphoma place for CAR T cells? And for bispecifics, what do you think about sequencing? What do we need to know? And are we gonna go on individualized strategies for certain subgroups? Maybe you can comment this.

Yeah, I think when we’re approaching a patient with the lymphoma, we have to acknowledge that they have several options usually available to them, and the majority of patients are going to do well. So can we do a better job risk Stratifying. So we identify those who need a more intensive approach not only from a side effect or safety profile, but also from a resource utilization standpoint. So I do think there is a role for CAR-T and where I use CAR-T and those young fit patients that are progressing quickly through active therapy, meaning they’re failing chemoimmunotherapy in a rapid style so similar to those POD24. Patients are those that look and behave like transformed disease but I biopsied them, and it’s still follicular lymphoma. I think there’s a larger role for bispecifics and particularly in that third line or later space. And so I think the off-the-shelf availability the, uh, we don’t have to manufacture these by specifics. Those are intriguing, and I highlighted why like motion. But the fact that it’s time-limited therapy also provides some attractiveness to it. But I think using how these agents work by T cell engagement, can we partner them with sort of rational combinations in follicular, the obvious combination partner in my mind is lenalidomide, so we know that it can combine safely. We have a randomized phase three underway right now looking at mose-len versus len-rituximab. So that will maybe shed light on what’s my preferred option. But I anticipate the by specifics will move into earlier lines and combination strategy, and we’ll still have a role for car T um, later on.

And what kind of questions do we need to answer so that we can better concept our clinical trials? So what do you think are still open questions that a sort of a challenge for thinking of the right sequence.

I think part of the problem is we usually focus our trial at a specific line of therapy, and we fail to acknowledge that how patients get to that line is incredibly heterogeneous. And so, being a little bit mindful about which patients were really trying to target in terms of an unmet need, I do think POD24 is an unmet need.

We could argue all day long about, you know, how important is it in terms of, uh, at third line? Is that as important as somebody who’s that second line who’s a POD24 status? Nonetheless, I do think in follicular without biomarkers that help us predict what therapy is going to be the preferred option. It really does still kind of depend on what their prior therapy was and how they responded to that prior therapy. So I’m going to be more intensive in a patient who’s progressing quickly through adequate therapy. I would be more gentle than someone who’s only had rituximab monotherapy, for instance. So we do personalize it. There’s an unmet need for biomarkers. And I think all these studies need to do a better job of really trying to do good quality of science. So we might one day have that. But in the real world, it’s really mostly clinically based.

Maybe you you can add and maybe also address the question. What do we know about bispecifics? What do they do to the T-cell compartment? And you know, if you can think of sequencing you can envision doing bispecifics prior to look out for is is maybe it enhances T cells, and we have a better T cell product for maybe CAR T cell therapy. Or maybe it’s reducing exhaustion. We should take the T cells out and then use bispecifics to bridge. Or maybe they are all in front line eventually. So maybe you can comment. What do you think? I’ll give some comments.

I hope that no one who is listening to this is an immunologist or I’ll get a lot of letters, I guess. Um, so, uh, uh, so a couple of things in terms of of, uh, sort of enhancing bispecific activity with immune strategies. Um, I know that, uh, some of the sponsors are looking at adding checkpoints or adding other bispecifics that have a second signal, like a CD28 signal, sort of augmenting that immune response in terms of does that then trigger T cell exhaustion. Um, you know, uh, and some of the data presented today, uh, the presumption was that the patients had failed car t due to some degree of T cell exhaustion because they hadn’t lost the target and again, and the by specific was still able to, um, give a potent T cell response. Um, and again with some of the data that was shown from maybe a different T cell population than the car t population.

So, um, so that suggests that that maybe it does not lead to, uh, t cell exhaustion, uh, may lead to some recovery, but, um, but then that begs the question. Why do two thirds of the patients don’t respond to the bispecific? So I think it’s it’s a complex biological question, and, uh, and I don’t have a good answer for that. I do think, though, that, uh, as we talked about talked about, uh, they may move earlier, Uh, in various treatment sequences and then, uh, selected populations. We may have very active, uh, conventional cytotoxic chemotherapy free regimens. Um, And so, in terms of missing data or data that needs to mature, we really need to know, um, how not only how durable, uh, how durable are these responses are there, uh, population of patients where the by specific would give that long lasting remission that we know, uh, fraction of patients with car t are getting, uh, and that I think also helps you sequence because you don’t want to give up on a therapy that may be cured.  Um, just because another therapy is easier or less toxic, but I think those are open questions. We don’t have that yet.

I think there was an important comment. So I would say the last word goes to you, Carmelo. So maybe you want to comment, and then we close the session. Positioning, this is a very difficult issue. Uh, I can give a few flesh from this.

First, I think that the we have to do a big effort to combine bispecifics with CAR-T. I don’t know. In which sequence, uh, when and why? Uh, as of today we have to stick to the registration of the drugs. And, uh, glofitamab will be registered as a third line therapy, so we would use it in the third line, but positioning if we want to approach a rational positioning, we need a huge studies looking at the mechanism of response, the mechanism of resistance. There are some of these projects already ongoing from the pharmacy side. Uh, genetic is very deeply involved in doing this study. There are academic projects. We are doing some, uh, omics study looking at potential biomarkers of response, or maybe even more important of resistance. Because if we know which patients may benefit more of a given drug, then we can speculate on positioning.

At the end of the day, the dream is to provide the majority of our patients with the chemotherapy free option therapeutic options. But this should be supported by a strong, rational and avoiding, uh, toxicity and maximizing a figure. See, And this is, uh, the nice part of our work at the end of the day.

All right, so I close the session. Thank you again for sharing your data and your thoughts. I think these are really exciting times for lymphoma. We have a new arsenal of weapons that are evolving, and they need to be combined and better understood. And I think even if we are not immunologists, we all have to have a look at the T cell compartment, which is really key of all these kinds of therapies. And with this, I’d like to close the session. Thank you.