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ERIC CLL 2026 | Could BTK degraders outperform pirtobrutinib against BTK resistance mutations in CLL?
Alexey Danilov, MD, PhD, City of Hope, Duarte, CA, discusses the potential of BTK degraders, such as tacabrutideg and bexobrutideg, to treat chronic lymphocytic leukemia (CLL), highlighting their ability to target multiple BTK mutations. Prof. Danilov believes these degraders may play a role in earlier lines of therapy, and notes that they have shown effectiveness against a range of mutations that pirtobrutinib does not address. This interview took place at the 2026 ERIC International Meeting in Barcelona, Spain.
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Transcript
Bexobrutideg and tacabrutideg are BTK degraders that are now being studied in randomized Phase III studies. And there are several studies ongoing, but the ones which are most interesting, I think, are the ones which randomize these drugs against pirtobrutinib. And there is a study for each of these for patients who have been previously treated with covalent BTK inhibitors...
Bexobrutideg and tacabrutideg are BTK degraders that are now being studied in randomized Phase III studies. And there are several studies ongoing, but the ones which are most interesting, I think, are the ones which randomize these drugs against pirtobrutinib. And there is a study for each of these for patients who have been previously treated with covalent BTK inhibitors. And I do believe that there is a place for BTK degraders, both of them, in early lines of therapy. Basically, what we see happening with BTK inhibition is emergence of BTK mutations, which in CLL tends to be one of the key mechanisms of resistance to BTK inhibitors, both covalent and also non-covalent. C481S mutation is, of course, the most common, which emerges with covalent BTK inhibition. However, other mutations also occur outside of C481S. And there are multiple mutations out there, some of them which actually render the kinase inactive. So it doesn’t have a function anymore, at least not the kinase function, but can still retain the scaffold function. And examples of these mutations are L528W and V416L. There is also a gatekeeper mutation, T474. And none of these mutations actually are addressed by pirtobrutinib. Pirtobrutinib was specifically designed to target C481S, which it does so very successfully. So meanwhile, the degraders are effective against all of the above mutations. And therefore, it is possible that as these mutations, we believe, pre-exist in form of small subclones, that using a BTK degrader will eliminate those subclones early and then delay resistance. The resistance will inevitably occur. We do see other types of mutations, such as residue A428, which ultimately happens with degraders. But because of their ability to target multiple types of mutations of BTK, I do think they have a future in earlier lines of therapy.
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