Pirtobrutinib Demonstrates Promise in Relapsed or Refractory Marginal Zone Lymphoma

Key Clinical Summary: 

• Design/Population: This phase 1/2 BRUIN analysis included 36 patients with heavily pretreated relapsed or refractory marginal zone lymphoma, most of whom had received prior anti-CD20 therapy, chemotherapy, and covalent BTK inhibitors.
• Key Outcomes: Pirtobrutinib achieved an objective response rate of 55.6%, with durable responses and a median progression-free survival of 16.6 months. Activity was maintained in patients previously treated with covalent BTK inhibitors.
• Clinical Relevance: These findings suggest that pirtobrutinib may provide a valuable treatment option for patients with relapsed or refractory MZL after multiple prior therapies. The favorable safety profile and activity in cBTKi-exposed patients support further evaluation of this noncovalent BTK inhibitor.

Results from the phase 1/2 BRUIN study demonstrated that pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), showed promising efficacy and tolerable safety in heavily pretreated patients with relapsed or refractory marginal zone lymphoma, including those previously treated with covalent BTK inhibitors (cBTKis).

“For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy with or in combination with chemotherapy (chemoimmunotherapy), with second-line options such as [cBTKIs]...However, management of relapsed and refractory [disease] remains a challenge,” stated Krish Patel, MD, Sarah Cannon Research Institute, Nashville, Tennessee, and coauthors.

In this study, 36 patients with extranodal (n = 6), nodal (n = 17), or splenic (n = 13) marginal zone lymphoma who had previously received anti-CD20 therapy (100%), chemotherapy (86%), or prior cBTKi therapy (72%) were treated with pirtobrutinib. The primary end point was objective response rate (ORR). Key secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

At analysis, the ORR was 55.6%, with 3 complete responses and 17 partial responses. Among patients previously treated with cBTKi therapy, the ORR was 53.8%. Median duration of response was 17.8 months, and median PFS was 16.6 months. At a median follow-up of 32.4 months, median OS was not estimable. Dose reductions occurred in 11.1% of patients, and treatment-related adverse events led to permanent discontinuation in 11.1% of patients.

These findings support pirtobrutinib as a promising therapeutic option for patients with relapsed or refractory marginal zone lymphoma, particularly in those with prior cBTKi exposure.

Source:

Patel K, Vose JM, Nasta SD, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi in R/R marginal zone lymphoma: Phase 1/2 BRUIN study. Blood Adv. Published online: January 16, 2026. doi:10.1182/bloodadvances.2025017489