Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase I/II BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with relapsed / refractory B-cell malignancies (clinicaltrials.gov 03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (N=40, 31.5%), specifically atrial fibrillation (N=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%) or death (5.5%). The most frequent treatment-emergent AE were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 21 mantle cell lymphoma (MCL) patients intolerant to prior BTKi, overall response rate to pirtobrutinib was 76.9% and 81.0%, respectively. Median progression-free survival for CLL/SLL was 28.4 months but was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.