SOHO 2025 | The potential of bispecific antibody-based combinations to improve outcomes in patients with FL

So this year at SOHO we had a great session on indolent lymphoma. It was very focused on novel immunotherapies, primarily T-cell based immunotherapies. And there are two big modalities in that space. One is CAR T-cell therapy, we didn’t really focus on that this year. And the other is bispecific antibodies and that was really front and center of most presenters’ talks. 

Dr Chris Flowers opened the session talking about frontline therapy of follicular lymphoma and how chemoimmunotherapy still really remains the standard and also about the search for new biomarkers of prognostication and efficacy of treatments. 

Following that Dr Laurie Sehn from British Columbia, Vancouver, delivered an outstanding lecture on the current state of play of bispecific antibodies in follicular lymphoma and indolent lymphomas in general. She covered both mosunetuzumab data, epcoritamab data, and odronextamab data. I should note, odronextamab is only approved in the European Union. It’s not approved, at least not yet, in the United States. The collection of those data really suggests that these drugs are paradigm-shifting drugs that really can revert the old dogma of less likely and less durable responses as the lines of therapies go through. You have patients now after three, four, five lines of therapy, they have a chance of response that’s in the 60 to 70 percent with durations that can exceed two years. This is not something we were used to seeing before. 

Following that lecture, I gave a presentation on combinations of bispecific antibodies with other agents and primarily my lecture focused on combinations of bispecifics with lenalidomide, which is an immunomodulatory drug that has a very prominent role already in the management of patients with follicular lymphoma, but the combination with bispecifics is particularly enticing because there certainly is a complementarity in their modes of action, there could be a synergism at an immunological level and the safety profiles don’t seem to overlap too much. So it’s really sort of a natural combination between these two drug modalities or the treatment modalities and the data are really very promising, although relatively early. In particular epcoritamab combined with lenalidomide and rituximab was tested in a large trial that we conducted with over 100 patients enrolled, 87% complete response rate, 80% two-year progression-free survival. Again, these are data that we were not used to seeing in patients with relapsed or refractory follicular lymphoma. So very encouraging. 

Similar data were presented with lenalidomide and mosunetuzumab, another bispecific antibody. Again, over two-thirds of the patients with a complete response, shorter follow-up, but certainly promising duration of response in that setting too. And all of these kind of Phase II promising trials led the way or paved the way for currently ongoing Phase III randomized trials, looking at comparisons between rituximab and lenalidomide alone versus rituximab and lenalidomide and epcoritamab. That’s the EPCORE FL-1 study that just completed accrual and the results of which will be presented at ASH this year. And on the other hand, lenalidomide compared with mosunetuzumab versus rituximab compared with lenalidomide in the CELESTIMO trial, then the results hopefully will be presented in the near future as well. 

But the excitement about bispecific combinations in follicular lymphoma ultimately translated into really the desire to test and push these combinations in the frontline setting. And so now we’re seeing a lot of trials testing either bispecifics alone, as we did at Memorial Sloan Kettering with mosunetuzumab, or in combination with lenalidomide or other drugs, and that’s true for both epcoritamab and odronextamab. And these single arm trials also pave the way for another set of Phase III trials in the frontline setting comparing bispecific antibody-based combinations against the standard of care which is, as I said before, chemoimmunotherapy. So I think in the next three to four years we have a good chance of seeing a profound shift in the standards of care in the early lines of therapy for patients with follicular lymphoma. 

What’s gonna happen to the future second and third line space? I think that’s really the big question. We’re really not able to answer it with the data today, but Dr. Zinzani with the fourth speaker really had a wonderful overview, gave a wonderful overview of all these novel agents, targeted therapies, antibody-drug conjugates, and then novel immunomodulators that are really occupying now the third line plus space in patients with follicular lymphoma and may become kind of our lifeline in a post-bispecific era, so to speak. So very exciting time we’re living and very exciting time ahead of us in the space of follicular lymphoma.

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