Pirtobrutinib (non-covalent BTK inhibitor) + venetoclax-rituximab lifts PFS vs VR in relapsed CLL/SLL

Pirtobrutinib (LOXO-305; a reversible/non-covalent BTK inhibitor) was added to fixed-duration venetoclax (BCL2 inhibitor) + rituximab (anti-CD20) in BRUIN CLL-322, an open-label, randomized Phase 3 trial in previously treated CLL/SLL (n=639; median 2 prior lines; 80% previously exposed to a covalent BTK inhibitor and 71% of those stopped their most recent covalent BTKi for progressive disease; venetoclax-naïve). At the Feb 2, 2026 data cutoff (median follow-up 27.3 months), IRC-assessed PFS favored PVR vs VR (HR 0.547, 95% CI 0.400–0.748; p=0.0001), with 24-month PFS 87% vs 72% and median PFS not reached vs 39.7 months—an improvement over the fixed-duration VR benchmark from MURANO (median PFS ~53.6 months in a broader relapsed/refractory population, but notably pre–covalent-BTKi era and not restricted to post-BTKi patients). Grade ≥3 TEAEs were similar (79% vs 73%), grade ≥3 tumor lysis syndrome was lower with PVR (1% vs 4%), atrial fibrillation/flutter rates were low (3% vs 3%), discontinuations due to related TEAEs were identical (5% vs 5%), and there were 5 treatment-related deaths (1 vs 4) (NCT04965493; global, 152 sites/22 countries; regimen includes a 3-cycle pirtobrutinib-rituximab lead-in before venetoclax).