iwNHL 2023 | Bispecific antibodies in NHL

Martin Hutchings: Hello, my name is Martin Hutchings. I’m here at the iwNHL in Miami, joined by Marion Subklewe, by Mazyar Shadman and by Krish Patel. We have just been taking part in a very interesting session over two hours on bispecific antibodies in non-Hodgkin lymphomas. We’ve been discussing the use in large B-cell lymphomas where there is approval of two drugs, but also in other indications and in different interesting combinations including perspectives for the future. We have a few minutes to give our take home messages for the audience at home. Marion, do you want to point out a few highlights?

Marion Subklewe: Yes. So I talked about blinatumomab. So that’s first in-class bispecific that was approved almost 10 years ago, and I think there are three lessons we can learn from blinatumomab that might also be applicable to the settings of lymphoma. So first of all, I think we’ve learned that bispecifics are more successful, but in earlier treatment lines. It was first approved in relapsed/refractory and was shown that in salvage one it works better than in later treatment lines. It also has been shown with blinatumomab that it works particularly well in the MRD setting, and there’s interesting data now evolving that best responses or even a benefit is seen for blinatumomab if combined in upfront de novo BCP-ALL in the MRD negative setting. So it also indicates probably that our technology is not super, with these patients still somehow at least MRD positive. I think the third aspect is as we are still not curing all patients- there are still residual cells- that we have to look at the T-cell compartments. So I think T-cell exhaustion, T-cell dysfunction, through chronic exposure to the bispecific is an issue. And I think we need to take into account when we combine our treatment strategies with bispecifics and sequence our bispecifics, that we watch out for the T-cell compartment. That we rather enhance T-cell function than depress T-cell function. One of the things that came out from our analysis is that there is also a necessity for treatment-free intervals. So that continuous exposure to the bispecific is probably detrimental for the T-cell compartment, but that having it on and off, either through the treatment cycles or through additional drugs like dasatinib, might be beneficial to increase efficacy.

Martin Hutchings: So these considerations are relevant in the context of all the different T-cell engagers. I must ask you though, you spent very little time on blinatumomab in lymphoma. Is there a role in the future for blinatumomab in DLBCL?

Marion Subklewe: I think the original studies in 2008 were actually in lymphoma and they didn’t see the same activity as in ALL. So that’s why the company at that time proceeded into the ALL context. I think they’re still struggling with putting up the dose and side effects, but now there’s also an application of Sub-Q. So, maybe they’re upping the dose at some point, but there are so many competitors, I’m not sure how far blinatumomab is going to go in lymphoma.

Martin Hutchings: Right. Dr Shadman, you opened with a difficult task, which was a comparison of the available data in the CD3xCD20 bispecifics. Would you summarize your thoughts on this?

Mazyar Shadman: Sure. So of course for large cell lymphoma, we have two great options now, both epcoritamab and glofitamab. In day-to-day practice, we have to make a decision and discuss with patients pros and cons of each approach. So, we had a chance today to discuss clinical efficacy, safety profile, and some logistical reasons with both drugs at high levels and the conclusion with the current follow-up: there doesn’t seem to be a major difference in terms of their efficacy or even safety profile. We discussed the fact that the long-term follow-up would be extremely important, focusing on infections and cytopenias. The two drugs have differences in terms of their delivery. One, epcoritamab, is treatment until progression, and glofitamab has a fixed duration therapy. So, maybe with the current follow-up, we are not capturing some of the differences in safety profile- but this is definitely something that we need to follow. Real world evidence would be important as well; some of these drugs will be used differently to what the clinical trial or the label recommendations are. So we will learn a lot about the experience in the community in the future too.

Martin Hutchings: Absolutely, still a lot to learn and even though these antibodies are similar in many ways, there are also big differences in their structure and the way that they are given. So you, Dr Patel, had the opportunity to tell us about odronextamab and plamotamab. Would you summarize the discussions around these drugs?

Krish Patel: Sure, happy to. So I’ll do odronextamab first. Odronextamab is another CD3xCD20 bispecific antibody. It currently has been studied in Phase II trials in DLBCL and follicular lymphoma. What we summarized and saw in that trial is that- very similar to other bispecific antibodies in large cell lymphoma- for example, in patients who have had prior CAR-T cell therapy, have had more than two lines of therapy, it’s a highly active bispecific. Overall response rates look to be around 50% or so, with roughly speaking, about half of patients achieving complete responses. And those appear to be potentially durable. So, comparable to what we’ve seen from other agents. But, I think, as was alluded to previously, they have differences in dosing intervals. CRS was seen in about half of patients, mostly Grade 1 or 2 during step-up for DLBCL. In follicular lymphoma, we see a similar story but a higher overall response rate. The overall response rate was approaching 80%, with the majority of those being complete responses. Safety looked very similar to DLBCL for the follicular lymphoma patients, mostly Grade 1 and 2 CRS. Odronextamab is actually being reviewed for potential approval- at least in the US- by the US FDA. So, maybe another tool to add to the toolbox and another sort of variation on bispecifics that we’ll have to incorporate in practice. Then, plamotamab is another CD3xCD20 bispecific antibody, also with a full length Fc receptor, still in dose optimization studies in Phase I trials. We presented data again in relapsed/refractory DLBCL. Slightly different cohorts than other bispecific trials, with a slightly later line median of four prior lines, a slightly higher fraction of post CAR-T cell therapy exposed patients. But again, similar, about 50% response rate, complete response rate around 25%, and similar CRS primarily during step-up dosing- common themes across the spectrum of CD3xCD20 bispecific antibodies.

Martin Hutchings: So I myself covered epcoritamab and glofitamab, showing data that are already known to most because these drugs are approved, in third-plus line treatment of large B-cell lymphomas based on frequent and deep responses, many of which are durable. But we went a bit further in our discussions towards what’s happening next- interest in combinations because they are highly combinable. That goes for odronextamab and plamotamab as well, eventually. We also ventured on to talk about the potential use of these antibodies in first-line treatment of large B-cell lymphomas. There are studies ongoing, so we don’t really have data yet. We have a bit of safety data that looks pretty good. Is this the answer to our next steps into first line treatment? Nobody really knows, but it was an interesting discussion. We also have friends that are absent here. We had Laurie Sehn who had to leave. She covered mosunetuzumab, mainly on its use in follicular lymphoma, and Ranjit Nair telling us new words from the interesting story of TNB-486, which is a CD3xCD19 bispecific antibody, which looks very promising in both intermediate and aggressive B-cell lymphomas. So with that, I will wrap this up. Thank you very much for your participation and thank you for your attention.