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.

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Publication Details

Journal
Blood Advances
Published
2025-08-22
DOI
https://doi.org/10.1182/bloodadvances.2024014975
Citations
2
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
3.25

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article

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

Bryone J. Kuss, Manish R. Patel, Jonathon Brett Cohen, Minal Barve et al.
2 citations
Blood Advances
Chronic Lymphocytic Leukemia Research
3.25
article

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

Bryone J. Kuss, Manish R. Patel, Jonathon Brett Cohen, Minal Barve, Talha Munir, Catherine C. Coombs, Ewa Lech‐Marańda, Kami J. Maddocks, Donald E. Tsai, Daigo Hashimoto, Krish Patel, Anastasios Stathis, Kaname Miyashita, Paolo Abada, Daisuke Ennishi, Andrew David Zelenetz, Fangfang Sun, Chan Yoon Cheah, Benoît Tessoulin, Shuo Ma, Julie M. Vose, Bita Fakhri, Minna Balbas, Sunita D. Nasta, Nirav Niranjan Shah, Pier Luigi Zinzani, Michael L. Wang, Yoshiaki Ogawa, Kensuke Kojima, Yuanyuan Bian
article en
2 citations

Abstract

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.

Blood AdvancesVol. 9(23)
Northwestern University (US), Tokai University (JP), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Emory University (US), Eli Lilly (United States) (US), Flinders University (AU), Palo Alto University (US), University of California, Irvine (US), Medical College of Wisconsin (US), Hokkaido University (JP), St James's University Hospital (GB), Sir Charles Gairdner Hospital (AU), Flinders Medical Centre (AU), Kettering University (US), Mary Crowley Cancer Research Center (US), Kochi Medical School Hospital (JP), Instytut Hematologii i Transfuzjologi (PL), National Hospital Organization Kyushu Cancer Center (JP), Ente Ospedaliero Cantonale (CH), Okayama University Hospital (JP), Sarah Cannon (US), Istituto di Ematologia di Bologna (IT), Florida Cancer Specialists & Research Institute (US), Azienda USL di Bologna (IT), Stanford Medicine (US), Hokkaido University Hospital (JP), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, The Ohio State University (US), University of Nebraska Medical Center (US), Kōchi University (JP), University of Pennsylvania (US), University of Bologna (IT), Stanford University (US), Nantes Université (FR)
Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Gilead Sciences, Celgene, TG Therapeutics, National Comprehensive Cancer Network, MEI Pharma, bluebird bio, BeiGene, Seagen, Ono Pharmaceutical, MorphoSys, Genentech, Pharmacyclics, Loxo Oncology, Janssen Pharmaceuticals, Daiichi Sankyo Europe
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Openalex Percentile: Top 7%
Chronic Lymphocytic Leukemia Research
3.25
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