ICML 2023 | Tolerability of next-generation BTK inhibitors: acalabrutinib, zanubrutinib and pirtobrutinib

I think we’ve got two head-to-head trials that have been published: the Elevate-RR and the ALPINE trials in CLL and as well as the ASPEN trial in Waldenström’s Macroglobulinemia comparing next generation BTK inhibitors, acalabrutinib and zanubrutinib with a first generation inhibitor, ibrutinib. We also now have pirtobrutinib, which was recently FDA approved for patients with relapsed/refractory mantle cell lymphoma after two prior therapies, including a covalent BTK inhibitor. And this is a very interesting drug, which is which is highly active and also associated with a favorable safety risk profile. In general, next-generation BTK inhibitors, you know, I’d say both the non-covalent BTK inhibitor, pirtobrutinib as well as the second generation covalent inhibitors appear to be better tolerated than ibrutinib. So the head-to-head trials, acalabrutinib and zanubrutinib are associated with fewer cardiac adverse events, most notably atrial fibrillation. And in the case of zanubrutinib in the ALPINE trial, there was a suggestion of improved progression-free survival as well. Of course, we have to remember that these were different trials, we really shouldn’t be comparing zanubrutinib and acalabrutinib across trials. There were differences in the proportion of patients with p53 aberrant CLL, there were also differences in the number of median prior therapies. For example, the median number of prior therapies in the ALPINE zanubrutinib trial was one versus two in the ELEVATE-RR trial. And so we really should try not to compare efficacy between acalabrutinib and zanubrutinib. However, it’s very clear that the second generation BTK inhibitors are associated with favorable safety compared with ibrutinib. And so in my practice, based on these data, I preferentially select zanubrutinib or acalabrutinib over ibrutinib for approved indications. The non-covalent BTK inhibitor pirtobrutinib is a very important drug in addition to the field and in my practice I use this in patients who either develop progression on a covalent BTK inhibitor or who become intolerant of a covalent BTK inhibitor and cannot be cycled to a different covalent BTK inhibitor that they subsequently are tolerant of. So, for example, if somebody develops myalgias on zanubrutinib or acalabrutinib, I will try the other covalent BTK inhibitor after appropriate dose reductions, if that’s insufficient and they continue to have intolerable toxicity, then I then go for an approved indication such as mantle cell or potentially for off-label use in CLL, then pirtobrutinib is an option.