Final Analysis of the BRUIN Phase 1/2 Study Assessing the Safety and Efficacy of Pirtobrutinib Monotherapy in Patients With MCL

Pirtobrutinib, a highly selective, non-covalent Bruton tyrosine kinase inhibitor (BTKi) previously demonstrated durable efficacy and tolerable safety following covalent (c) BTKi therapy in heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL). Here, we report final results from the global Phase 1/2 BRUIN trial evaluating pirtobrutinib in patients with R/R MCL, with and without prior cBTKi exposure. Endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. BRUIN enrolled 166 patients with R/R MCL (data cutoff: 27Jan2025). In the cBTKi-exposed cohort (n = 152), median study follow-up time was 16.1 months (range, 0.5-69.6). The ORR was 49.3% (95% CI, 41.1-57.6). Median DOR was 21.6 months (95% CI, 9.2-27.2). Median PFS was 5.6 months (95% CI, 5.3-9.2; 36-month rate, 19.9%). Median OS was 23.9 months (95% CI, 17.3-51.5; 36-month rate, 43.2%). In the cBTKi-naïve cohort (n = 14), median study follow-up time was 44.5 months (range, 1.6-67.1). The ORR was 85.7% (95% CI, 57.2-98.2). Median DOR was 42.7 months (95% CI, 25.8-not estimable [NE]). Median PFS was 44.6 months (95% CI, 16.7-NE; 36-month rate, 58.7%). Median OS was NE (36-month rate, 76.2%). The most frequent any-grade treatment-emergent adverse events (TEAEs) were infections (44.0%), fatigue (31.9%), and diarrhea (22.9%); the most frequent grade ≥ 3 TEAEs were infections (21.1%) and neutropenia (15.1%). Grade ≥ 3 hemorrhage (3.0%) and any-grade atrial fibrillation/flutter (3.6%) were infrequent. With extended follow-up, pirtobrutinib continued to demonstrate efficacy and favorable safety in cBTKi-exposed and -naïve R/R MCL. Trial Registration: ClinicalTrials.gov identifier: NCT03740529.