iwNHL 2025 | Novel therapies and ongoing trials in NHL: advances in antibody-based combinations

Laurie Sehn

So we’re here at the iwNHL and we just finished a session on novel combinations in lymphomas. I’m Laurie Sehn from BC Cancer and I’m joined here by my colleagues, Dr Juan Alderuccio from University of Miami and Dr Gilles Salles from Memorial Sloan Kettering. And I have to say that just my general impression of the session is that we are being overwhelmed with new data that really is, I think, changing how lymphoma is being managed in real time. And, you know, we spent a big part of the discussion reviewing some of the novel agents that have now emerged as standard of care and some of the exciting trials that have moved forward with these novel agents that, you know, we’ll have data forthcoming. I, in this session, discussed the new data of tafasitamab combinations, where we know it was initially approved in the L-MIND trial for relapsed/refractory DLBCL and is now available out as a platform for patients in the relapsed/refractory setting. But more recently, we had the InMIND trial where it was compared in a head-to-head trial against R-squared for relapsed/refractory follicular lymphoma, which has recently earned it an approval. So the combination of tafasitamab, lenalidomide, and rituximab now is a new approved option for patients with relapsed/refractory follicular lymphoma after at least one prior line of therapy because the head-to-head trial demonstrated improvement in response rates, CR rates, as well as its primary endpoint of progression-free survival. And the comparable toxicities were relatively similar, maybe with a slight increase in viral infection that were generally mild, but is now available as an additional option. And then we heard other discussions. Juan, you discussed some of the really exciting data on loncastuximab.

Juan Alderuccio

Yeah, thank you, Laurie. We discussed the LOTIS-7 clinical trial, which combines loncastuximab with glofitamab in patients in second-line class large B-cell lymphoma. Showing in the initial analysis of 40 patients, no new safety signals with this combination. And in a preliminary analysis of 30 patients, a high response rate that at the time of data cut-off appears to be durable. Now this study is expanding to enroll a total of 100 patients and we expect to have this recruitment finalized by early 2026. And we also discussed data on follicular lymphoma with loncastuximab in combination with rituximab. This was initiated as a single-centered study and responses were high in the relapsed/refractory setting across different high-risk groups. And now the study transitioned to a multi-center study, also aiming to enroll a total of 100 patients. And we, in an updated analysis with the data cut-off in mid-September, we observed high responses and durable responses with a two-year PFS about 80 percent. So we also hope to finalize the enrollment in first quarter of 2026 and report this data at ASH next year.

Laurie Sehn

That is a really, I think, exciting combination for follicular lymphoma and maybe a little bit surprising, but it’s nice to see that we’re going to have even more data on additional patients moving forward.

Juan Alderuccio

Yeah, and also what we are doing in this multi-center phase to fix the treatment duration to six cycles, aiming to decrease the toxicity associated with cumulative doses of loncastuximab.

Laurie Sehn

Good. We certainly look forward to that. And Gilles, you reviewed some of the data on polatuzumab combinations, and I have to say the discussion was quite lively.

Gilles Salles

Yeah, I mean, polatuzumab vedotin, as we know, as drugs that has been combined with bendamustine-rituximab, you did the study with RCHP, you’re drawing vincristine, and now it’s being developed in combination with bispecifics. I think there are two parts of this discussion. The first one is the differential effects that was observed in the POLARIX study, where a patient with a genetically determined ABC cell-of-origin appears to have a very large benefit of this drug, with almost 30% difference in progression-free survival and more than 10% in overall survival, while there was little or no apparent benefit in the other subgroup. And how do we translate that? How do we apply that in clinic? Was it detrimental to some patients? It’s a little bit unclear. There are also probably some other patients with GCB phenotypes that may benefit and others not. So there is an open question here. And we heard during the meeting in the spring that in the POLARGO study that used polatuzumab vedotin in combination with R-GEM-OX, there was no difference in showing an overall survival and progression-free survival benefit. there was no difference in patients that were GCB and ABC. So there is still complicated data here. And I think people may choose one way, depending on what is labeled in their country, depending on what’s authorized and things like that. But I think it raised to me more fundamentally the question of how do these drugs work? What explains the efficacy? Is that the binding to the antigen? Is that the internalization? Is that the activity of MMAE. And, you know, the data experimental for polatuzumab suggested the antigen expression. But in the same session, we heard this trial of brentuximab vedotin plus R-square in relapsed/refractory DLBCL showing that in patients with virtually no CD30 expression, there was a benefit of adding this drug. So that’s one of the question modificacy.

And the second one is, you know, we have all these trials being developed in the frontline study. We have the efficacy in the second line of bispecific plus polatuzumab vedotin, either mosun in a randomized trial or glofit in Phase II trial. And we have, as just said by Juan, the loncastuximab with glofit. So how are we going to sequence that? And it will depend probably at this time we have R-CHOP and Pola-R-CHIP approved in the US and available in other jurisdictions with some limitations. There are a wave of about six, seven, eight randomized trials that are going to be delivering results with tafasitamab, with acalabrutinib, with bispecific antibody in the next one to two years. And how are we going to choose? How are we going to optimize what we give to patients in terms of toxicity, durability? And I think that’s an interesting question and also the question of sequence. If you use bispecific before, what are you going to use after? If you lose MMAE-containing antibody drug conjugate, such as, for instance, polatuzumab, can we use zilvo, which is a ROR1 MMAE-containing drug in the relapsed setting, which has also interesting results, or should we use a different toxin? So I think all these questions are now emerging. Some have data to answer, some are data to be confirmed. And I think we’ll need to understand it raised a question that, you know, what is best for our patient beyond what is approved and how to best sequence. And that will probably keep us in a very lively situation, in how to optimize the treatment of patients with B-cell lymphoma.

Laurie Sehn

For a very long time. One of the things we also heard in this meeting was a very nice review of DLBCL genetic classification as delivered by Margaret Shipp. And I think there’s such a paucity of data in terms of using it as a predictive classifier in the relapsed/refractory setting. I mean, many of our relapsed/refractory trials have maybe been a little too small to probably, you know, sort of mine that kind of predictive data. But we now have some larger Phase III trials that have just emerged. And I think we still have yet to see any of this potential correlative analysis that might make us a little smarter in terms of which patients are preferentially benefiting in the relapsed/refractory setting. But I think that’s going to be essential to be built into all trials so that we can at least, you know, go beyond, you know, our very rudimentary practice of sort of empiric management.

Gilles Salles

I will emphasize that, you know, Dr Margaret Shipp gave this beautiful presentation from the papers that was recently published and what was done in POLARIX and all the questions here and how to implement this genetic classification in clinics remains to be determined. But I think it’s probably relatively urgent because if we assume, and maybe we are wrong, but that we may have an MMAE-containing agent in the first line with chemotherapy plus a bispecific, the patient that will unfortunately experience relapse will have maybe some quite specific particularities. And we may have used CD20-directed therapies, MMAEs, others. And we may have to go back to something we have a little bit neglected in the last 5-10 years, which are targeted molecules, given the PHOENIX and ROBUST data. But we know that we’re making progress with these targeted molecules, maybe again there are combinations that are here. So I think continuing to explore the genetic of this lymphoma is important because we may identify some subset that may benefit particularly of some of these drugs.

Laurie Sehn

Juan, maybe I’ll ask you a question. So most of us are looking to get away from maybe further chemotherapy, at least in the relapsed/refractory setting with these novel agents that are now available. Yet we’ve had this series of clinical trials that have really been built on a GEMOX backbone. In your clinical practice, are you eager to give the GEMOX platform with these novel agents? Would you, you know, if you had access to glofit-GEMOX, would you give it or would you be just as happy to maybe jump right to glofit alone?

Juan Alderuccio

So, yeah, in the United States, glofit-GEMOX is in NCC guidelines. So we have access. And that has been my practice in those patients that for some reason are not an issue for a clinical trial. and use as a standard of care the combination of GEMOX with glofitamab and help with a few patients and with excellent responses and very quickly. So it’s unfortunate it has not been approved and hopefully the sponsor can provide the necessary data to have the regulatory approval. But definitely I think it’s a very potent combination that will improve patient outcomes.

Gilles Salles

If you look at the bispecific antibody, glofitamab and epcoritamab, which had exactly the same CR rate in the pivotal Phase II, 39-40%, you see that when combined with either cytotoxic agents, if that’s GEMOX with glofitamab, but also with epcoritamab, the epcoritamab GEMOX Phase II was published, or with an antibody drug conjugate, lonca, polar, and maybe others in the future, you raise the bar of complete response by 10-15%. It’s a little bit to be determined if this is the same CR that lasts. I was encouraged by the update of the STARGLO, the trials that compare glofitamab, GEMOX versus R-GEMOX, showing that it looks like after one year when we were off therapy, the curve between one and two years didn’t change much for those patients in CR, suggesting that maybe some patients in the relapsed setting may be cured by this regimen, because that’s the main question when we have CAR-T available, is that are we offering bispecific combination, or are we sticking to CAR-T because we have five years data with CAR-T? Again, interesting question for future debates.

Laurie Sehn

So maybe we’ll just finish up by, I’ll ask you, of the agents that we discussed in this last session, which were largely antibody-based therapies, what trials that are ongoing are you most excited about seeing the results from? Gilles?

Gilles Salles

Well, I think that the trials with currently polatuzumab vedotin, which is a drug I discussed, are available. You know, POLARIX was just published with five years update. We like to see the publication of the mosun-pola, which probably is quite practical in the community. And the rest are Phase II, the POLARGLO trial. You know, it’s a combination in relapse setting. I don’t see really where it fits in the armamentarium. So I would like to see a little bit more data with the mosun-pola. And I will see what other combination will be developed. and available as comparative trials.

Juan Alderuccio

Yeah, I think also I agree. And also the frontline study with Pola-R-CHIP plus glofitamab versus Pola-R-CHIP. That’s going to be very interesting and see, because we’re going to be most likely future trials based on that data. And also the combination of loncastuximab glofitamab, I think is interesting after we expand the current cohort to 100 patients and we have longer follow-up data to see how durable are these responses. And I think also the ctDNA data is going to help until you have longer follow-up to see how deep are their responses. And we can start to challenge some standard of care like CAR T-cell in the second-line setting.

Laurie Sehn

Well, I think we’re going to have no shortage of things and controversies to discuss in the future. I think the next big trial to read out, at least the big Phase III trial, will likely be the frontline trial, which you pointed out, which will compare tafasitamab, lenalidomide, and R-CHOP versus R-CHOP. So to be continued, we’ll see. I think it’s really a quickly evolving area. But the exciting part has been that, you know, all of these options have opened up and are likely to open up are really showing an impact in terms of favorable patient outcomes. Well, thank you for joining me. You know, a very interesting discussion.

Juan Alderuccio

Thank you.

Gilles Salles

Thank you for having us.

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