Pirtobrutinib (non-covalent BTK inhibitor) drives 82.5% ORR in R/R Waldenström’s at ~3-year follow-up

Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase (BTK) inhibitor evaluated as monotherapy in the open-label, multicentre Phase 1/2 BRUIN trial (NCT03740529) in relapsed/refractory Waldenström’s macroglobulinemia after prior BTK inhibitor–containing regimens. In 80 patients (median 3 prior lines; 79% previously exposed to a covalent BTK inhibitor), investigator-assessed ORR by IWWM-6 criteria was 82.5% (CR 1.3%, VGPR 10.0%, PR 61.3%, minor response 10.0%) with median follow-up 35.0 months; ORR was 81.0% in prior covalent-BTKi patients vs 88.2% in BTKi-naïve patients. Grade ≥3 TEAEs occurred in 71% (most commonly anaemia 24% and neutropenia 19%); TEAEs led to dose reduction in 5% and discontinuation in 15%, with 1 treatment-related death (necrotising pneumonia) among 5 TE deaths total (6%)—notably, depth of response (VGPR/CR 11.3%) appears lower than covalent BTKi benchmarks like ibrutinib long-term VGPR ~30% and zanubrutinib VGPR ~28% in ASPEN, though cross-trial comparisons are confounded by post-covalent BTKi biology and heavier pretreatment.