iwNHL 2025 | An update on BTK-targeting therapies in NHL & CLL: combinations, BTK degraders, and ongoing trials

Meghan Thompson

Hi, my name is Meghan Thompson from Memorial Sloan Kettering Cancer Center in New York, New York. 

Alexey Danilov:

And I’m Alexey Danilov from City of Hope in Los Angeles, California. 

Meghan Thompson

So we just wrapped up a session here at iwNHL 2025 talking about BTK targeting therapies, covalent BTK inhibitors, non-covalent inhibitors, and this emerging class of BTK degraders. So, Alexey, let’s start with the first BTK inhibitor, ibrutinib. Where do you see ibrutinib now in your clinical practice? And what do you think about its future in the years to come? 

Alexey Danilov:

Yeah, so ibrutinib is still obviously approved in therapy of chronic lymphocytic leukemia. And it’s interesting now that it has been removed from the market for therapy of mantle cell lymphoma. We have a slew of positive studies in mantle cell lymphoma, which are paradigm shifting. The TRIANGLE study, which tested ibrutinib in patients with previously untreated mantle cell lymphoma, essentially put a huge question mark over transplant as a treatment modality for MCL and placed ibrutinib and BTK inhibitors in frontline therapy of MCL. In this case, ibrutinib was used in a time-limited fashion for two years, and those patients who received ibrutinib actually had better overall survival than the control arm, whether or not they received autologous stem cell transplant. And then the second study, also a really important study, ENRICH, which randomized patients with mantle cell lymphoma to ibrutnib-rituximab versus chemoimmunotherapy, showed improvement in progression-free survival, arguably in patients where the control arm received RCHOP. So the outcomes were similar between ibrutinib, rituximab, and BR. But nevertheless, there was a benefit for the whole group. There was a benefit for sure among patients who had received RCHOP in the control arm. And overall, at least similar outcomes with BR. So again, placing ibrutinib as a potential frontline therapy for mantle cell lymphoma, even without chemoimmunotherapy. So where does that leave us? Can we extrapolate that data and say use acalabrutinib or zanubrutinib in place of ibrutinib? I really don’t know, but I do see it happening in clinical practice now. And what also helps is the ECHO study, which randomized patients to BR or BR plus acalabrutinib, did show positive data in favor of acalabrutinib with BR, improvement in progression-free survival in previously-untreated mantle cell lymphoma. Of course, that study used continuous acalabrutinib, but nevertheless, it at least gives us an opportunity to use acalabrutinib in frontline therapy of MCL when we want to add BTKi to a chemoimmunotherapy regimen. So there is a lot of changes which are essentially precipitated by the studies of ibrutinib in mantle cell lymphoma now. And there are also a significant number of studies of acalabrutinib in combination with, say, lenalidomide and rituximab as a chemo-free approach in mantle cell, acalabrutinib-rituximab as a simplified regimen in mantle cell. So there are all these new regimens, chemo-free regimens coming in mantle cell, which are trying to displace chemoimmunotherapy from treatment of that disease, just like we did in CLL. So let me ask you, Meghan, what do you think of pirtobrutinib data? There’s been quite a bit of data recently in CLL and also mantle cell lymphoma with pirtobrutinib. Where do you think this drug stands? 

Meghan Thompson:

Yeah. So I think, you know, it started as all drugs do as monotherapy in the relapse setting. In CLL, the outcomes are a little bit more durable with monotherapy than, for example, mantle cell lymphoma, where it does seem that there’s a short duration of response, particularly after prior covalent BTK inhibitor. I think that it has a role in CLL as monotherapy, but it’s often a bridge to something else because we’ve seen that acquired resistance, some of which is mediated by new BTK mutations cropping up or PLC gamma 2 mutations in a subset of patients potentially, that patients respond, but it’s not durable. So it’s not going to be years and years. It is being tested in CLL in the initial study as well as a mantle cell lymphoma in combination. So for example, pirtobrutinib, venetoclax, obinutuzumab in CLL has very good response rates in most patients as a fixed-duration therapy. And then there’s ongoing study with pirtobrutinib in treatment naive mantle cell at MD Anderson in combination, for example, with rituximab, another study combination with venetoclax. So there are attempts to move into the frontline setting. We’ll see data pretty soon actually from a randomized trial in CLL, pirtobrutinib versus ibrutinib. We don’t know the data yet, but that study included both treatment-naive and relapsed patients. So I think in CLL, the story is a little bit different because the bar is very high because outcomes are very, very good with the initial regimens we have. And one of the concerns is that moving pirtobrutinib earlier, depending on how the resistance mechanisms are in frontline therapy might prohibit future use of covalent BTK inhibitor because there does appear to be some overlapping mechanism, but we really don’t know what the resistance mechanisms are with combinations. This might not be an issue. And also with frontline therapy, we haven’t seen that. So we’ll kind of have to wait. But it is a dynamic space with a lot of ongoing studies. And I think it speaks to, as we have targeted agent combinations, we’re really going to have to think differently about different patients in each line of therapy, what their prior therapy was, what their remission duration after that was, whether we can reuse some of these agents or similar agents in an orthogonal class like covalent and non-covalent BTK inhibitors. 

Alexey Danilov:

So an interesting approach was suggested today, actually combining non-covalent and covalent BTK inhibitors at the outset, so giving them together. I think Steve Treon mentioned his preclinical work where there was an improved downregulation of pro-survival signaling in lymphoid cells. What do you think of that approach? 

Meghan Thompson:

Yeah, I think it’s definitely intriguing. I think I’m not sure how it’ll play out in clinical practice. I think, you know, small pilot cohorts are the way to find out. You know, of course, we’d have to make sure the safety of the two is fine. They have pretty overlapping toxicities. Pirtobrutinib is pretty well tolerated, but we don’t know whether side effects will be augmented, of course, with two different drugs. And then thinking about kind of the resistance mechanisms, you are targeting, you know, BTK, although the binding sites of different, you know, the different classes are different on BTK itself, you know, in some sense, maybe it could prevent resistance, but you might end up also selecting out for resistant clones, I could see if this continues over time. And then, of course, the question is always, particularly in CLL, is a combination better all at once, or will you get more, in a disease where you’re not curing, in terms of sequence? So I think it’s definitely intriguing, but we’d have to see whether some of this preclinical hypothesis-generating work would actually play out that way in patients. 

Alexey Danilov:

Yeah, so the combinations with BTK inhibitors is something that’s been discussed quite a bit in this session, and it is believed that some of the BTK inhibitors may have these immunomodulatory effects. Krish Patel talked about how acalabrutinib may modulate tumor-associated macrophages in a positive way. So there is a rationale to combine BTK inhibitors with CAR T-cells, with bispecific antibodies, and, certainly, such efforts are now ongoing. 

Meghan Thompson:

Yeah. Alexey, tell us a little bit about BTK degraders. I know you’ve done some work about BTK degraders and their immunomodulatory effects in the lab, and then these agents are now coming to the clinic. So what do you foresee in different BTK degraders, of course, depending on their structure. I know the two Nurix compounds, one has Icarus degradation, for example, another doesn’t. Tell us a little summary of why you think that might be important, both as monotherapies and then as combinations moving forward. 

Alexey Danilov:

Yeah, absolutely. So you’re right, Meghan. So not every BTK degrader is created equal. Most degraders that are in development, including BGB-16673, ABBV-101, and NX-5948, which now has a name of bexobrutideg. They are all clean BTK degraders, which they bind cereblon, but they do not modulate cereblon, so then they do not have the second lenalidomide-like property. And it seems like these degraders work really well in CLL. You presented really good data, high activity in CLL patients. But also, there is an opportunity to engage the second mechanism, immunomodulatory mechanism, and we have generated some preclinical data where NX-2127, which has now a name of zelebrudomide, actually has strong immunomodulatory activity. We specifically studied T-cells. So it induces T-cell repolarization toward the inflammatory phenotype. It enhances immunological synapse formation. It enhances cytotoxicity. And so it does have this clear immunomodulatory effect, which then can be co-opted in combination studies. For example, I would think that BTK degraders with IMiD capability might lend themselves better to combinations with, you know, bispecific antibodies, any type of immunotherapy that you can think of. Not to say that IMiD-incapable or like non-immunomodolatory BTK degraders couldn’t do that as well, potentially. But it is very, very clear that IMiD-capable BTK degraders have this role. So we will see how these combination studies are being designed. Zelebrudomide is currently still in the dose escalation phase, so we’ll have to wait for a little bit to get to that point. But Meghan, you talked about a number of studies being developed with BTK degraders by BeOne medicines. Could you tell us what those studies will be? 

Meghan Thompson:

Yeah, so different for different disease subgroups. So in CLL actually already started as a phase three, the phase two study is ongoing as an expansion of the phase one CaDAnCe-101trial, which is the monotherapy study in relapsed CLL. There’s also a phase two study going on in Waldenstrom’s macroglobulinemia. And then in CLL, actually a phase three study in heavily pretreated CLL patients is BGB-16673 versus investigator’s choice of idelalisib, venetoclax-rituximab, or bendamustine-rituximab. Different in different parts of the world requirements in terms of prior therapies, depending on the approvals in that country. But that’s more for, for example, in the United States, a patient who’s seen prior covalent BTK inhibitor, BCL2 inhibitor, and non-covalent inhibitor. And then there’ll be an upcoming phase three study in CLL that’s been announced. It’s BGB-16673 against the control arm of pirtobrutinib. And this will be in patients who have received at least a covalent BTK inhibitor and discontinued that after progressing. So a couple of phase three studies. And then there are combination in the early phase that started enrolling different cohorts. So a cohort looking at combination with sonrotoclax, which is a BCL2 inhibitor, zanubrutinib, so BTK degrader and covalent BTK inhibitor, and then two bispecific antibody cohorts, mosunetuzumab and glofitamab combination. So early days, but starting to bring the degrader in combination with other mechanisms. 

Alexey Danilov:

Yeah, and maybe we will close by discussing Waldenstrom’s macroglobulinemia, LPL. Steve Trian gave a talk on that. There’s so much exciting development in that space. Both degrader molecules have high activity in relapsed/refractory Waldenstrom’s macroglobulinemia. And there are many studies designed using zanubrutinib, venetoclax, also showing very high preliminary efficacy data. So this is certainly becoming a very rich, exciting field in Waldenstrom’s. 

Meghan Thompson:

Absolutely. Yeah, no, I think the take-home message is that now we have these new BTK degraders. We’re now kind of learning to use our targeted therapies, covalent BTK inhibitors, BCL2 inhibitors, now the degraders, along with all the other immune-based therapy, CAR-T bispecifics, and learning how to fit these together in rational combinations. 

Alexey Danilov:

Yeah, so BTK seems to be a target that keeps giving. 

[both laugh]

Meghan Thompson:

Agree.

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