Nirav N. Shah, MD, MSHP, discusses bexobrutideg and what the BTK degrader could bring to chronic lymphocytic leukemia management.
On the heels of encouraging data from the phase 1a/b NX-5948-301 trial (NCT05131022), the ongoing phase 2 DAYBreak CLL-201 trial (NCT07221500) could add further evidence to support
“If we can give a drug that can actually prevent mutations or help us not deal with the relapsing/remitting course by offering [BTK degraders] earlier, that would be a boon to patients. The story doesn't end here; this is the beginning of the story for BTK degraders,” Shah said in an interview with OncLive®.
In the interview, Shah explained what separates BTK degraders from BTK inhibitors, detailed the potential importance of DAYBreak CLL-201 for the CLL treatment paradigm, and outlined previous data for the BTK degrader, with the most recent phase 1 update presented at the
Shah is an assistant professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin in Milwaukee.
Shah: Targeting an enzyme called BTK has become pivotal in the treatment paradigm for [CLL]. The problem is that, eventually, CLL can escape these BTK inhibitors. They can develop mutations within the BTK enzyme that make them resistant to our current class of [BTK inhibitors]. [Therefore,] new classes of BTK[-directed agents] were developed; some are called noncovalent [BTK inhibitors], but even that class can eventually run into resistance.
BTK degradation is a completely different way of targeting BTK that is active against BTK wild-type and BTK resistance mutations. [BTK degradation] really goes after the entire enzyme by using ubiquitination to degrade the entire BTK enzyme and disrupt both the scaffolding and kinase functioning, unlike current BTK inhibitors. [BTK degraders] could be potentially beneficial, at least initially, to those patients who have seen and progressed on currently available BTK inhibitors. Degradation may be a methodology to overcome resistance mutations that occur in those patients.
Quite a bit of data has been presented on bexobrutideg, [especially at the] 2026 EHA Congress, where basically they presented updated efficacy and safety data as part of their ongoing phase 1a/b trial in CLL. [What these data] showed in this patient population is that now more patients have been treated [with bexobrutideg]—142 patients—with a promising safety and efficacy profile. There were few grade 3 or higher treatment-emergent adverse effects [TEAEs], and there were no new cases of atrial fibrillation reported, which is a common toxicity we've seen with BTK inhibitors.
Patients in the phase 1a [portion of the trial achieved] an overall response rate of 83%. These were patients who were highly refractory, [with] a median of 4 prior lines of therapy. [It was] very exciting to get more and more data with [bexobrutideg] at the 2026 EHA Congress.
[DAYBreak CLL-201] is a pivotal phase 2 clinical trial, and hopefully, if [the trial is] positive, it will lead to an accelerated approval to make [bexobrutideg] available to patients who need it right now. [DAYBreak CLL-201] is a trial that currently is [enrolling] patients with relapsed or refractory CLL, but they must have been treated with the available classes of drugs.
When we think about key available classes of drugs, we think of covalent BTK inhibitors like acalabrutinib [Calquence], zanubrutinib [Brukinsa]; noncovalent BTK inhibitors like pirtobrutinib [Jayprica]; and a BCL2 inhibitor in venetoclax [Venclexta]. This is a tough group of patients [to treat]. If they have progressed on all classes of approved options, you really don't have a lot of treatment options available to you. That's where DAYBreak CLL-201 is an opportunity for that patient population to get a drug that can maybe overcome these resistance mutations that may have occurred after exposure to other BTK inhibitors. [DAYBreak CLL-201] is actively accruing, and it's just an important trial to have available to patients that have exhausted the currently available options.
None of us have a crystal ball into the future, but what I'm hoping that [DAYBreak CLL-201] will show is that [bexobrutideg can be] a new treatment option that will show efficacy in this highly refractory group of patients with CLL. I'm not too worried about the safety of [bexobrutideg], because the safety has been well defined in these 142 patients who have been exposed to bexobrutideg [in the phase 1 study]. We're seeing a consistent, well-tolerated drug, and having been an investigator on the original trial, I can tell you from my own patient experience that people have tolerated this drug well.
I have some patients of my own who have now been on [bexobrutideg] for years, [thus], the safety part is not a concern. Triple-refractory CLL is just difficult to treat, and we're going to learn a lot about how efficacious this drug is in that clinical setting. If [bexobrutideg] meets the benchmarks like we hope that it does, then it [could become] FDA-approved as another weapon in our arsenal against CLL.
Everything is initially going to come in and be a sequential therapy [in later lines]. [Bexobrutideg is] going to be given like it was studied in the clinical trial, as an option after failure of other BTK-targeting agents. However, [development] is not stopping with this with just this one clinical trial. Ultimately, we want to see if it is better than currently available therapies, and we're hoping that a positive study will lead to additional positive studies that will move BTK degraders as an earlier line of treatment.
We've studied it in a phase 1 clinical trial, and having a phase 1 clinical trial can look different than a phase 2 or phase 3 study where you have more patients. The inclusion criteria may be a little bit broader so more patients can come on board; [therefore,] the number one question [remaining with BTK degraders] is: do the phase 1 data hold up? Does this drug look as good when they study it in this triple-refractory or triple-exposed group of patients with CLL?
We know that combinations in CLL are very exciting, as we use BTK inhibitors with venetoclax. Do we use a BTK degrader with venetoclax? Could we give an anti-CD20 antibody with a [BTK degrader]? How [BTK degraders] combine with other drugs is another fascinating area that I'm interested in seeing as part of this development.
We’re very early in the timeline for [BTK degraders and bexobrutideg]. It's been recently developed, and it's not approved yet. If I had to predict, it's going to be another weapon for us to have against CLL, but regarding how we use it, how we combine it, what line of therapy [it will be in], that story is still yet to be written.
