EHA 2025 | The use of pirtobrutinib after a covalent BTKi in pretreated CLL

Pirtobrutinib is a non-covalent BTK inhibitor which has been designed to overcome resistance to covalent BTK inhibitors such as ibrutinib, acalabrutinib and zanubrutinib. Resistance to these drugs is often mediated by a mutation in BTK, bruton’s tyrosine kinase, specifically at the C481 site, and pirtobrutinib is able to overcome this resistance. BRUIN CLL-321 randomized patients with relapsed/refractory CLL, who previously were treated with a covalent BTK inhibitor, at least one line of therapy, to pirtobrutinib or standard of care, which included either bendamustine-rituximab or idelalisib-rituximab. There was improvement in progression-free survival in favor of pirtobrutinib among these patients. It was interesting to see that patients who were double refractory, meaning who progressed on both BTK inhibitor and venetoclax, had somewhat shorter time to next therapy than patients who had not been exposed to venetoclax. But nevertheless, pirtobrutinib exhibited high efficacy in this patient population with high overall response rate. It also showed very favorable safety with very low risk of cardiovascular adverse events, low rate of atrial fibrillation, less than 5% over the course of this therapy, and really no new safety signal over the time of the follow-up of the study. 

So in many community clinics and academic clinics, pirtobrutinib is becoming the go-to regimen for double-refractory patients. And I’m also looking forward to being able to use this drug in patients who only progressed on BTK inhibitors and haven’t been exposed to venetoclax yet as we certainly need more treatments for these patients as well.

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