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

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.