Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi in R/R marginal zone lymphoma: phase 1/2 BRUIN study.

Clinical Snapshot

Key Findings

• P Value: Not reported for primary endpoint

• Effect Size: Complete response rate 8.3%, partial response rate 47.2%

• Primary Outcome: Objective response rate 55.6% (95% CI: 38.1-72.1%)

• Nnt Or Sensitivity: ORR in prior cBTKi patients: 53.8% (95% CI: 33.4-73.4%)

• Confidence Interval: ORR 95% CI: 38.1-72.1%; DOR 95% CI: 7.4-NE; PFS 95% CI: 9.0-22.1 months

Clinical Application

Oral therapy with manageable toxicity profile; 11.1% dose reductions and 11.1% discontinuations Would require TGA approval and PBS listing; fills unmet need in R/R MZL where limited options exist beyond rituximab and chemotherapy Heavily pretreated R/R MZL patients, including those with prior covalent BTK inhibitor therapy

Abstract

Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies with a remitting and relapsing course. For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy or in combination with chemotherapy (chemoimmunotherapy), with second-line options including covalent Bruton tyrosine kinase inhibitors (cBTKi). However, management of relapsed and refractory (R/R) MZL remains challenging. Pirtobrutinib, a highly selective, noncovalent BTKi has shown promising efficacy and tolerability in poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here, we report the safety and efficacy of pirtobrutinib in MZL from the phase 1/2 BRUIN study. Endpoints included investigator-assessed objective response rate (ORR) by Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 36 patients with R/R MZL (extranodal [n = 6]; nodal [n = 17]; splenic [n = 13]), median age was 68 years (range, 22-83) and median prior lines of therapy were 3 (range, 2-10). The ORR was 55.6% (95% confidence interval [CI], 38.1- 72.1), including 3 (8.3%) complete responses and 17 (47.2%) partial responses. Median DOR was 17.8 months (95% CI, 7.4 to nonestimable [NE]), and median PFS was 16.6 months (95% CI, 9.0-22.1). With median follow-up of 32.4 months (IQR, 28.0-41.3), median OS was NE (95% CI, 29.5-NE). The ORR for patients with prior cBTKi therapy was 53.8% (95% CI, 33.4-73.4). Pirtobrutinib was well tolerated with dose reductions in 4 patients (11.1%) and permanent discontinuation due to treatment emergent adverse events in 4 patients (11.1%). Pirtobrutinib showed promising efficacy and safety in patients with heavily pretreated R/R MZL, including prior cBTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.

References

1. 1.Patel, K., Vose, J. M., Nasta, S. D., Brown, J. R., Maddocks, K. J., Woyach, J. A., Shah, N. N., Fakhri, B., Tessoulin, B., Ma, S., Jagadeesh, D., Lech-Maranda, E., Coombs, C. C., Patel, M. R., Rhodes, J. M., Ujjani, C., Hoffmann, M. S., Cheah, C. Y., Munir, T., Lewis, D., Scarfò, L., Eyre, T. A., Alencar, A., Cohen, J. B., Zelenetz, A. D., Tsai, D. E., Li, M., Bian, Y., Abada, P., Balbas, M., & Zinzani, P. L. (2026). Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi in R/R marginal zone lymphoma: phase 1/2 BRUIN study. Blood Advances. https://doi.org/10.1182/bloodadvances.2025017489