ESH CLL 2026 | The evolving role of non-covalent BTK inhibitors in CLL

I’m not sure non-covalent BTK inhibitors will replace covalent BTK inhibitors. I think we’ll sort out which is best for each patient and circumstance. Also, non-covalent BTK inhibitors include pirtobrutinib and drugs like nemtabrutinib that have different selectivity and probably will be ultimately different or used in different patient populations. So I think the question is less like, will non-covalent just wholesale replace covalent BTK inhibitors? I don’t think that’s going to happen. But I think we will learn more uses for non-covalent BTK inhibitors, especially pirtobrutinib that now is frontline data. But you have to think about who’s the patient? Is the selectivity really important? Also, when we know that pirtobrutinib can result in mutations in BTK that make the covalent BTK inhibitors ineffective, and we don’t know yet what it looks like to try to use a covalent BTK inhibitor after pirtobrutinib, I think as we get that data, we’ll figure out more about this. But when you have someone that’s young and you’re looking at decades of lifespan, you might not want to do something like pirtobrutinib first because we know that works in resistance. But if you have someone in their late 80s, that’s probably an excellent idea, limiting toxicity, not worrying about decades in someone in their late 80s. Not that someone in their late 80s can’t live decades, but I think there’s some expectations there about lifespan that are different. So I think it’s less replacement of covalent BTK inhibitors and more just seeing how this plays out for individual patient populations.

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