Pirtobrutinib Demonstrates Durable Clinical Activity in Relapsed or Refractory Waldenström Macroglobulinemia

Clinical Summary: 

• Design/Population: The phase 1/2 BRUIN trial evaluated pirtobrutinib in patients with relapsed or refractory Waldenström macroglobulinemia, including patients 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.
• Clinical Relevance: These findings support pirtobrutinib as a potential treatment option, particularly following covalent BTK inhibitor therapy.

Results from the phase 1/2 BRUIN trial demonstrated that pirtobrutinib shows durable clinical activity among patients with relapsed or refractory Waldenström macroglobulinemia, including those previously treated with covalent Bruton tyrosine kinase (BTK) inhibitors.

“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 multi-center, open-label study, 80 adult patients with relapsed or refractory Waldenström macroglobulinaemia received once daily pirtobrutinib in 28-day cycles (phase 1 = 18; phase 2 = 62), with 200 mg established as the recommended phase 2 dose. Primary end points included objective response rate (ORR) and safety. Response was assessed according to the Sixth International Workshop on Waldenström Macroglobulinemia criteria.

At a median follow-up of 35 months, 91% of patients received 200 mg of pirtobrutinib. The ORR was 82.5% with complete responses in 1.3% of patients, very good partial responses in 10% of patients, partial responses in 61.3% of patients, and minor responses in 10% of patients. The ORR was 81% in patients previously treated with a covalent BTK inhibitor (79%) and 88.2% in covalent BTK inhibitor-naïve patients.

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