Management of Chronic Lymphocytic Leukemia in 2020 - Episode 10

Distinguishing Features Among BTK Inhibitors


William Wierda, MD, PhD: I’d like to touch a little bit on one last BTK [Bruton tyrosine kinase] inhibitor that was mentioned at this meeting. Constantine Tam, MBBS, MD, gave 2 presentations, and I think the Australians have done a lot of work with this compound so maybe, Stephen, you can comment on your experience with zanubrutinib and where we think that fits into our treatment.

Stephen Opat, MBBS: Zanubrutinib is again another second-generation BTK inhibitor. I think it’s similar in adverse effect profile to acalabrutinib. It’s, I think, approved in the United States now for mantle cell lymphoma. There are a number of trials in CLL [chronic lymphocytic leukemia], including at ASH [the American Society of Hematology annual meeting] 2019, an update on the use of the drug in patients with 17p-deleted CLL. I can say that both acalabrutinib and zanubrutinib in terms of efficacy seem similar to ibrutinib. The difference really is in terms of adverse effects. There are a number of head-to-head trials that will actually answer whether there is a difference in efficacy. I guess if a drug has a favorable toxicity profile, then adherence may be better, and therefore you might see an efficacy difference. So we’re waiting for those to read out. I think it’s a useful drug. It also seems like a reasonable option, but follow-up is a lot shorter than what we know with ibrutinib.

William Wierda, MD, PhD: It’s going to make it even harder I think for us to choose treatments because we’re going to have 3 different, probably in the near future, available BTK inhibitors. What are some of the things we think about, and what do you think are going to the distinguishing features between the different irreversible BTK inhibitors?

Shuo Ma, MD, PhD: All of the BTK inhibitors we have discussed so far, the ibrutinib first generation, and the second generation, including acalabrutinib and zanubrutinib, all of those are irreversible BTK inhibitors because they’re binding to BTK through covalent binding. Now, the next generation of BTK inhibitors are actually reversible. The idea behind that is that for patients who are treated with a BTK inhibitor, one of the main resistance mechanisms is a mutation in the BTK gene itself at binding site to the first and second-generation BTK inhibitors. So once the BTK acquired that mutation, they’re no longer able to bind to either the first or second-generation inhibitors through covalent binding.

Whereas the reversible BTK inhibitor, for example, one of the presentations at ASH 2019, an oral presentation, is LOXO-305. That’s one example, and there are several other products that are in research, studying the reversible BTK inhibitors. A reversible BTK inhibitor can potentially overcome the resistance at the binding site because they don’t have to bind through covalent binding. And indeed, the abstract that was presented in December actually showed that the LOXO-305 was able to even overcome the patient who has a known BTK mutation and known resistance to ibrutinib, to show clinical benefit.

Transcript Edited for Clarity