Pirtobrutinib Demonstrates Durable Clinical Activity in Relapsed or Refractory Waldenström Macroglobulinemia

Results from the Phase 1/2 BRUIN Trial

Clinical Summary: 

• Design/Population: The phase 1/2 BRUIN trial evaluated pirtobrutinib, a noncovalent Bruton tyrosine kinase (BTK) inhibitor, in patients with relapsed or refractory Waldenström macroglobulinemia, including those previously treated with covalent BTK inhibitors.

• Key Outcomes: Pirtobrutinib demonstrated high response rates regardless of prior covalent BTK inhibitor exposure and was associated with a manageable safety profile. Responses were durable across treatment subgroups.

• Clinical Relevance: These findings support pirtobrutinib as a promising treatment option for relapsed or refractory Waldenström macroglobulinemia, particularly in patients previously treated with covalent BTK inhibitors.

Results from the phase 1/2 BRUIN trial demonstrated that pirtobrutinib produced durable clinical activity in patients with relapsed or refractory Waldenström macroglobulinemia, including those previously treated with covalent Bruton tyrosine kinase (BTK) inhibitors, supporting the noncovalent BTK inhibitor as a potential treatment option in this setting.

“Covalent BTK inhibitors have advanced the treatment of Waldenström macroglobulinaemia… However, the occurrence of progression, intolerance, and acquired resistance are not fully understood,” stated Lia Palomba, MD, Memorial Sloan Kettering Cancer Center, New York, New York, and coauthors. 

In this multicenter, open-label trial, 80 adult patients with relapsed or refractory Waldenström macroglobulinemia received once-daily pirtobrutinib in 28-day cycles, including 18 patients enrolled in phase 1 and 62 in phase 2. A dose of 200 mg once daily was established as the recommended phase 2 dose. The primary end points were objective response rate (ORR) and safety. Responses were assessed according to the Sixth International Workshop on Waldenström Macroglobulinemia criteria.

At a median follow-up of 35 months, 91% of patients received pirtobrutinib 200 mg daily. The ORR was 82.5%, including complete responses in 1.3% of patients, very good partial responses in 10%, partial responses in 61.3%, and minor responses in 10%. Response rates were consistent regardless of prior covalent BTK inhibitor exposure, with ORRs of 81% among previously treated patients and 88.2% among BTK inhibitor-naïve patients.

Grade ≥3 treatment-emergent adverse events occurred in 71% of patients. The most common events included anemia (24%) and neutropenia or decreased neutrophil count (19%). Treatment-emergent adverse events led to 4 dose reductions and 12 treatment discontinuations. Five treatment-emergent deaths were reported, including bacterial sepsis, intracranial hemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly with pneumonia, and treatment-related necrotizing pneumonia.

“Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed,” concluded Dr Palomba et al. 

Source: 

Palomba ML, Patel MR, Eyre TA, et al. Safety and activity of pirtobrutinib in patients with relapsed or refractory Waldenström macroglobulinaemia: 5-year follow-up of the open-label, multicentre, phase 1/2 BRUIN trial. Lancet Haematol. Published online: May 2026. doi: 10.1016/S2352-3026(26)00037-2