Multinational phase 1-2 trial of pirtobrutinib for relapsed or refractory Waldenström macroglobulinema: 5-year follow-up of BRUIN

The phase 1-2 BRUIN trial, at 29 sites across eight countries, evaluated the non-covalent BTK inhibitor pirtobrutinib in patients with relapsed or refractory Wladenström macroglobulinemia (R/R WM). Eligible patients were 18 years or older, and had an ECOG performance status 0-2. In phase 1, patients received 100-300 mg oral pirtobrutinib once daily and the recommended phase 2 dose of 200 mg once daily was determined. The phase 2 primary endpoint was investigator-assessed objective response rate (ORR). Among 80 patients with R/R WM (18 in phase 1 and 62 in phase 2, median age 68.5 years, 65% male, median number of previous lines of systemic therapy 3, 79% received previous covalent BTK inhibitors), the ORR was 82.5% (95% CI 72.4-90.1), with one patient reaching complete response, eight (10.0%) reaching very good partial response, 49 (61.3%) reaching partial response, and eight (10.0%) reaching minor response. The ORR was 81.0% for those who received previous covalent BTK inhibitors and 88.2% for those who were covalent BTK inhibitor-naïve patients. Grade 3 or higher treatment-emergent adverse events occurred in 71% of patients. Treatment-emergent deaths were reported in five (6%) patients. Adverse events leading to dose reduction and discontinuation occurred in 5% and 15%, respectively. The authors conclude that pirtobrutinib was highly active and well tolerated among patients with R/R WM.