ASH 2021 | BTK sequencing: Purpose of 1st, 2nd and 3rd line BTKs

The second-generation ones that have the same mechanisms, zanubrutinib and acalabrutinib, there was recently a randomized Phase III comparing ibrutinib to acalabrutinib, and zanubrutinib has the same going on. For the ibrutinib-acalabrutinib, it was in high-risk patients that were relapsed/refractory and was powered for non-inferiority, but the progression-free survival was the same, the hazard ratio was one and it was not inferior. So the efficacy at least of acalabrutinib and ibrutinib seems similar, but the toxicity is less. So I think it is likely and is already happening with the other approved drug acalabrutinib, where that is replacing use of ibrutinib for a lot of patients. Not all of them, because ibrutinib is a daily dose, the other one is twice a day, so there’s some minor differences that matter for an individual, so I do think zanubrutinib and acalabrutinib are likely to replace ibrutinib.

The reversible ones that’s not yet clear. So drugs like pirtobrutinib, which I’m sure you’ve heard about, ArQule 531, there’s a couple other drugs that are in development. Those have been studied in relapsed/refractory patients and largely those that are BTK inhibitor exposed, so it’s not yet clear that those offer an advantage that they should replace the initial ones. In fact, resistance to the reversible ones maybe would confer resistance to the covalent ones, so it might be better to sequence the ibrutinib, acalabrutinib, zanubrutinib, whatever of those and then go to reversible ones. So I don’t know that the new type of BTK inhibitors is yet going to move up to that point. I know as we get more data, I’m very certain it’ll be studied early in the disease course for assigned therapies, et cetera, but I don’t know that the goal is necessarily just to straight up replace those with the different mechanism BTK inhibitors.