Non-Covalent vs Covalent BTK Inhibitors: What’s Best of Patients | Jennifer Woyach, MD

My name is Jennifer Wyack. I'm a CLL specialist from the Ohio State University, and we're here at the American Society of Hematology 2025 Annual Meeting. At ASH this year, we presented data from the Bruin CLL 314 study, which was a head-to-head of the non-covalent or reversible BTK inhibitor pyrtobrutinib compared with the covalent BTK inhibitor ibrutinib. So ibrutinib is the first in class of the Brutin's tyrosine kinase or BTK inhibitors that really transformed the treatment of CLL as well as many other hematologic diseases. We know that when patients take drugs like ibrutinib or the second generation inhibitor as a calibrinib or xanibutinib, they can develop resistance due to mutations that can occur in the spot in the protein where the drugs bind. So pyrtobrutinib was actually initially designed to overcome resistance to those other BTK inhibitors. However, with further study, it's extremely potent, it's a very effective drug, and it is very, very well tolerated because it's a really selective drug for the target. And so the hypothesis here is because of that effectiveness and because of the safety that it actually might be a better drug than the covalent BTK inhibitors. So again, randomized trial where patients were either put on treatment with pyrtobrutinib or with ibrutinib, and it included patients with both treatment naive, so this was their first CLL treatment or those people who had had other CLL treatments in the past. And the primary objective or the primary purpose of the study was to look at response rate and to see whether responses were as good with pyrtobrutinib as they are with ibrutinib, and then subsequently to see if they were better. And then further than that, looking at the progression free survival, so kind of remission duration of pyrtobrutinib compared with ibrutinib. So at this meeting, we were able to present the first data, which was the overall response data, but then some exploratory or kind of preliminary look at the progression free survival. So in terms of response rate, pyrtobrutinib was non-inferior and was actually better than ibrutinib in the entirety of the patient population that was treated, including those people with relapsed to refractory CLL, as well as those who had never been treated for CLL. We also saw with the progression free survival, at least at this early time point, it was actually trending towards being better for pyrtobrutinib than ibrutinib, again, across all patients and in people with both untreated CLL and previously treated CLL. And then the safety of pyrtobrutinib looked really excellent, similar to the previous studies. And compared with ibrutinib, there were lower rates of heart toxicity, so hypertension or high blood pressure was lower with pyrtobrutinib, and atrial fibrillation was less likely in people who were treated with pyrtobrutinib. As well, pyrtobrutinib required less reductions in the dose compared to ibrutinib. So overall, I think this is a very exciting study at showing both the safety and the effectiveness of pyrtobrutinib in people who had never been treated with a BTK inhibitor before. I think one caveat, though, is that we don't know much about sequencing if you try to use pyrtobrutinib first. So can you go back and use a covalent inhibitor like ibrutinib, acalabrutinib, or xanabrutinib after somebody has been treated with pyrtobrutinib? And I think we're not sure that that is the case, that you can do that. So for right now, I think that the use of pyrtobrutinib in people who haven't had a BTK inhibitor before will be just for selected patients. And then when we have more data in a few years, we may be able to expand that recommendation for more patients. If our videos have helped you in any way, and you're able to, please consider making a donation to help us continue this important work. Your gift will go three times as far when we reach $500,000 by the end of the year. Every contribution, big or small, makes a difference, and we're deeply grateful for your support.