iwNHL 2024 | ADCs in B-cell lymphomas: emerging data and novel targets

Laurie Sehn:

So we are here at the iwNHL in Nice, France. And we just had a very interesting session on antibody-drug conjugates. I’d like to introduce my colleagues. I’m Laurie Sehn from BC Cancer.

This is Alex Herrera from City of Hope. We’ve got Juan Pablo Alderuccio from the University of Miami, and Paolo Caimi from Cleveland Clinic. And it is, I think it was a fascinating session, because the world is changing very quickly in the development of new drugs in diffuse large B-cell lymphoma and B-cell lymphomas broadly. But certainly, you can’t understate the potential of antibody drug conjugates. And Alex, maybe we’ll start with you, because you presented some really interesting new data on brentuximab vedotin in DLBCL.

Alex Herrera:

So brentuximab vedotin is an antibody drug conjugate directed against CD30. And we typically think about using this drug in Hodgkin lymphoma, or in T-cell lymphomas, where CD30 is widely expressed. But there’s variability in the expression of CD30 in diffuse source B-cell lymphoma. So it hadn’t had so much traction in the drug development for diffuse large B-cell lymphoma.

But there were some early studies, showed moderate response rates in the 40% range. Ultimately, it was combined with brentuximab with lenalidomide. And that seemed to improve the response rate, independent of CD30 expression. And so, ultimately, there was this randomized Phase III study of BV with R-squared lenalidomide rituximab, compared to R-squared, as the control arm.

And fascinatingly, it actually improved progression-free survival, it improved overall survival in patients with relapsed refractory DLBCL compared to the control arm. And that was, again, independent of CD30 expression patients on the trial. Actually, two-thirds of the patients on the trial didn’t have CD30 expression that was visible by routine immunohistochemistry.

Really interesting. I think a lot of the patients on the trial had had prior CAR T-cells, had had prior bispecific antibodies. So a little bit more of an applicable population to our present-day relapsed/refractory DLBCL patients that we see. I think it remains to be seen how to use this drug. I think probably, not going to supplant CAR T-cells, obviously, but maybe an option for patients who have progressed after CAR T-cells, or are ineligible for CAR T-cells, or don’t have access to CAR T-cells, and maybe have progressed, or don’t have access to bispecific antibodies. I think it’s at least interesting to think about trying to use this drug in the real world, and seeing if we can replicate the trial results.

Laurie Sehn:

Yeah, well I think really interesting data. I think was somewhat surprising to a lot of people when it came out. And a really interesting discussion, in that many patients were CD30 negative, as you said, how is the drug really working? But certainly there’s going to be no shortage of the need of additional options, and looking forward to seeing what it does in the real world.

And then Paolo, you talked about an update on loncastuximab tesirine, which is obviously a newly available drug to many people. I still don’t have it in Canada, but looking forward to using it.

Paolo Caimi:

Yeah, so that’s yet another ADC. Compared to brentuximab, it’s an antigen that we know is in B-cells and multiple drugs that target CD19 in that area. What is different with the other antibody drug and immunoconjugates is that the payload is different. It releases a DNA-damaging agent, compared to most ADCs that have anti-microtubule activity.

And it’s been validated on a Phase II study, with the diffuse large B-cell lymphoma, where the activity was complete response about 25%, and partial response of 25%. And the more recent data suggests that there are still patients that can be complete responders for a long period of time, although still a minority of patients.

And the retrospective real-world data suggests that there’s a use in later lines of therapy, with some activity for diffuse large B-cell lymphoma. So it’s definitely an agent that’s available to us for treating patients with aggressive lymphoma. And it’s being developed, like many other antibody-drug immunoconjugates with combinations with other drugs.

Where I think this class really shines, is when you can combine it with either another antibody like rituximab or with chemotherapy. And they seem, because of the toxicity profile, combinable. Dr Alderuccio’s study, he completed himself, with a combination with rituximab with activity in follicular lymphoma, reached an overall response over 90% and complete response very close behind. So that’s something that is very promising for the class of agent, and for the target, for a drug that is relatively easy to administer, with a special toxicity profile, where photosensitivity is an issue, but less hematologic toxicity and no neuropathy.

Laurie Sehn:

Yeah. And I think we’re really excited about the new combinations that are being tested. But I think it can’t be understated, that in the real world, what we also need are just very well-tolerated agents that can be delivered safely to elderly patients. And I think that, certainly lonca, has that nice balance of risk-benefit. I think that’s very desirable in that setting.

Paolo Caimi:

Correct. And the Phase II study showed that their elderly patients were able to tolerate it similarly than younger patients.

Laurie Sehn:

And then, of course, I updated the data on polatuzamab vedotin, where we know that it was initially approved in combination with bendamustine and rituximab, for relapsed/refractory DLBCL patients. And then more recently tested, moved forward in the POLARIX trial, where it replaced vincristine and the Pola-R-CHP combination head-to-head against R-CHOP.

And really, it’s been the first trial in the upfront setting of DLBCL that has met its primary endpoint of progression-free survival, that was improved for Pola-R-CHP.

We spent quite a bit of time talking about the intriguing signal that it may have preferential activity in ABC subtype, and what mechanism that might be by. And I think right now, it probably is being used in the intent to treat population, but should it be, if we have more trials coming forward in the upfront setting, do we then start to select patients out based on what we think the best option is?

And then of course, polatuzumab is being tested in numerous ongoing trials, combined with R-ICE in the salvage setting pre-transplant. We have combinations with R-Gemmox against R-Gemmox alone. And then, I think a very intriguing combination of mosunetuzumab and polatuzumab as a non-chemotherapy-based approach for relapsed DLBCL that’s showing a lot of promise in being tested in a phase three trial against R-Gemmox.

And then finally, Juan Pablo, you brought everything home by really discussing the future. So we’ve got really important drugs that have already made it to the market, but there’s certainly a lot in development and other targets that are being explored for antibody-drug conjugates.

Juan Pablo Alderuccio:

Yeah, several targets has been developed on ADC, targeting those antigens in the last couple of years. I think the most interesting is an AbbVie ADC, which targets CD19. But what is novel is the payload, which modulates the glucocorticoid receptor. The ADC, after attached to CD19, is internalized into the lymphoma cells and modulates the glucocorticoid receptor producing apoptosis.

These compound show significant activity in preclinical models, in GCB and ABC DLBCL subtypes, and is currently being testing in a Phase I clinical trial. So hopefully, we will hear about this compound in the near future.

What is, the rest of the ADCs with novel targets, it’s very difficult to know where they fit currently in the B-cell lymphoma landscape, with the currently approved compounds and the bispecifics, that are very quickly changing the treatment landscape.

I think another interesting compound is an ADC which targets TCRT1 in T-cell lymphomas, which show significant preclinical activity, and hopefully clinical trials will start to be developed in the near future aiming to improve the outcome in this difficult to treat population.

Laurie Sehn:

Great. Well I think the one thing that I took away from this session was that we’re probably just scratching the surface with the potential for ADCs in lymphomas in general. And I look forward to all of these studies coming to fruition, and of course, exploring these novel agents as well, which I think, as much as we are making progress, we know that there’s room for additional drugs of merit.

Juan Pablo Alderuccio:

Absolutely.