FDA approved pirtobrutinib (Jaypirca) for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma in adults without del(17p), expanding the noncovalent BTK inhibitor into first-line use. The decision was based on results from the phase 3 BRUIN CLL-313 trial, in which pirtobrutinib significantly delayed disease progression versus bendamustine plus rituximab. At an estimated median follow-up of 28 months, median progression-free survival was not estimable with pirtobrutinib versus 33.5 months with the control arm (HR 0.20; P<.0001). Overall survival was immature, with three deaths in the pirtobrutinib group and 10 in the comparator group. The study allowed crossover after progression. Clinicians now have a new targeted option when selecting initial therapy for CLL/SLL patients, particularly those who may be less suited for chemoimmunotherapy given age and comorbidity profiles. Lilly’s investigator Jennifer A. Woyach framed the approval as a shift in initial treatment decisions, not just later-line use.