Pirtobrutinib is a new therapy for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), especially in patients who have received multiple prior treatments. Unlike older BTK inhibitors, pirtobrutinib is a selective, noncovalent BTK inhibitor that binds reversibly and remains effective against the common C481S mutation causing resistance.
In the Phase 1/2 BRUIN trial, it achieved an overall response rate of 81.6% and median progression-free survival of 19.4 months. Patients intolerant to prior BTK inhibitors responded at 76.9%, with fewer heart-related side effects and only 2.5% discontinuing treatment. The Phase 3 BRUIN CLL-321 trial showed superior progression-free survival (14.0 vs. 8.7 months) and longer time to next therapy compared with standard care, with fewer severe adverse events.
Pirtobrutinib also shows promise in combination with venetoclax and in Richter’s Transformation, though emerging resistance highlights the need for molecular testing. It represents a major advance for relapsed or resistant CLL/SLL and may expand into earlier treatment settings.