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

Relapsed/refractory (R/R) follicular lymphoma (FL) is a chronic disease often requiring multiple lines of therapy. Covalent Bruton tyrosine kinase inhibitor (BTKi) monotherapy has resulted in variable response rates, yet patients invariably experience relapse. While newer therapies such as bispecific antibodies and chimeric antigen receptor T-cell (CAR T cell) therapy are available, patient access and eligibility remain challenging. Here, we report the safety and efficacy of pirtobrutinib, a noncovalent (reversible) BTKi monotherapy in a R/R FL cohort from the multicenter phase 1/2 BRUIN study. Key end points included investigator-assessed overall response rate (ORR) per Lugano 2014 criteria, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Among 48 patients with FL, the median age was 64.5 years (range, 37.0-85.0). Patients had received a median of 3 (range, 1-12) prior lines of therapy. The ORR with pirtobrutinib was 52.1% (95% confidence interval [CI], 37.2-66.7), and median DoR was 10.2 months (95% CI, 3.7-25.7). Median PFS was 5.8 months (95% CI, 3.8-8.1), and median OS was not estimable, with a median follow-up of 35.2 months (interquartile range, 31.1-41.8). The estimated DoR, PFS, and OS rates at 24 months were 33.3% (95% CI, 15.9-51.9), 25.6% (95% CI, 13.9-39.1), and 75.1% (95% CI, 59.5-85.4), respectively. Pirtobrutinib was well tolerated, with 2 patients (4.2%) discontinuing treatment due to adverse events (AEs; 1 treatment-related) and 4 patients (8.3%) having dose reductions due to AEs (all treatment related). Pirtobrutinib showed promising efficacy and was well tolerated in this cohort of patients with heavily pretreated R/R FL, warranting further investigation. This trial was registered at www.clinicaltrials.gov as #NCT03740529.