Treatment Options for Patients with CLL Progressing on Covalent BTK Inhibitors

Dr. Paul Ghia: So I mentioned about mutations in acalabrutinib and ibrutinib, but do you want to tell us something about what is happening with zanubrutinib?

Dr. Brian Hill: So with zanubrutinib, we don't have as much data. And I agree with the, the statement that we wouldn't dare to use a covalent BTK inhibitor after resistance to another covalent BTK inhibitor. So it is important to describe the resistance mechanisms after acalabrutinib, and we have some data on resistance mechanisms after zanubrutinib treatment. So, recently published in Blood Advances, there was a paper that examined the BTK mutations, and in particular relative to ibrutinib, at least in this small series, we saw about half of the cases had a three N 528 mutation, which may be important in the selection of subsequent therapies because as we'll hear next, well, maybe you can tell us about the non-covalent BTK inhibitors and how these are differ from the covalent one.

Dr. Paul Ghia: Yes, indeed. What you mentioned is very relevant. So it is true that the BTK inhibitors is an evolving field. So we have novel molecules, the third generation to which we are referring, particular pirtobrutinib, for which we have more data now. And there is also some access around the world in different countries and also the other molecules in ibrutinib. It is true that the type of mutation in BTK may help in the future to understand better about the sequencing between the different molecules. You mentioned about the L 528, which does not seem to be molecular rising with ibrutinib and zanubrutinib, ibrutinib and acalabrutinib. In only one case, probably in our study we saw that mutation while instead it's more frequent with zanubrutinib and also with pirtobrutinib. So we might really develop other sequencing strategies between all these molecules. And we were talking about pirto because pirtobrutinib and zanubrutinib are non-covalent inhibitors. So they don't bind persistently to the BTK molecule. But that's mechanism probably does not explain entirely why they are effective after first second generation BTK inhibitors, probably because they bind still in the ATP pocket, which is relevant for the function of BTK, but in a different position compared to ibrutinib, zanubrutinib and acalabrutinib. So at the end of the day, patient who were refractory to ibrutinib and probably also had the BTK inhibitors they responded to pirtobrutinib. That's the message of the BRUIN study, phase one, two study where the patient who were refractory in two third of the cases to ibrutinib or to a previous BTK inhibitor, then they responded in two thirds of the cases to pirtobrutinib, which is very reassuring because we know that we can somehow salvage our patient even if they fail a prior BTK inhibitor.