Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed/Refractory Follicular Lymphoma: Results from the Phase 1/2 BRUIN Study
Authors: Shah Nirav N. , Zinzani Pier Luigi , Wang Michael L. , Nasta Sunita D. , Lech-Maranda Ewa , Ogawa Yoshiaki , Fakhri Bita , Kuss Bryone , Miyashita Kaname , Patel Krish , Coombs Catherine C. , Ma Shuo , Patel Manish , Barve Minal A. , Tessoulin Benoit , Stathis Anastasios , Kim Won Seog , Ennishi Daisuke , Hashimoto Daigo , Kojima Kensuke , Zelenetz Andrew D. , Cohen Jonathon B. , Vose Julie M. , Maddocks Kami J. , Munir Talha , Sun Fangfang , Bian Faith , Tsai Donald E. , Abada Paolo , Cheah Chan Y. 
Published: December 2023

Background: Follicular lymphoma (FL) is a chronic and incurable disease requiring multiple lines of therapy for patients (pts) with relapsed/refractory (R/R) disease. Covalent Bruton tyrosine kinase inhibitors (cBTKi) have transformed the management of select B-cell malignancies, in particular chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, despite the transformative impact in CLL and MCL, the efficacy of single-agent cBTKi has been limited in pts with R/R FL, with an overall response rate (ORR) of 20.9% to 37.5% (Gopal et al, J Clin Oncol, 2018; Bartlett et al, Blood, 2018). Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency and has a favorable oral pharmacology that enables continuous BTK inhibition throughout the once-daily dosing interval. Pirtobrutinib has demonstrated promising efficacy and tolerability in pts with poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here, we report the safety and efficacy of pirtobrutinib in a cohort of pts with R/R FL from the BRUIN study (NCT03740529).

Methods: Pts with previously treated B-cell malignancies were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter phase 1/2 BRUIN study. FL diagnosis required pathologic review of an adequate biopsy. Key endpoints included investigator-assessed ORR per Lugano 2014 criteria, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. A data cutoff date of 05 May 2023 was utilized.

Results: Among the 48 pts with FL, 45 (94%) pts received the recommended phase 2 dose of pirtobrutinib (200 mg once daily) as their starting dose. Pts had a median age of 64.5 years (range, 37.0-85.0), were mostly male (60%, n=29), and had a median of 3 (range, 1-12) prior lines of therapy. Most pts (81%, n=39) had Ann Arbor stage III/IV disease. The Follicular Lymphoma International Prognostic Index (FLIPI) risk was low (0-1) in 9 (19%) pts, intermediate (2) in 13 (27%) pts, high (3-5) in 23 (48%) pts, and missing in 3 (6%) pts. Overall, 43 (90%) pts had received chemotherapy plus an anti-CD20 antibody, 17 (35%) pts had received a PI3K inhibitor, 14 (29%) pts had received lenalidomide, 6 (13%) pts had received an autologous stem cell transplant, and 4 (8%) pts had received CAR T-cell therapy. Of the 4 (8%) pts who had received a prior cBTKi, 3 discontinued due to disease progression and 1 discontinued for intolerance. The ORR was 50.0% (95% confidence interval [CI], 35.2-64.8), including 7 (14.6%) complete responses and 17 (35.4%) partial responses (Figure). An additional 12 (25.0%) pts had stable disease. Among 4 pts who had received prior cBTKi, 3 achieved partial response and 1 had stable disease. With a median follow-up of 18.4 months (interquartile range, 10.1-21.0) among 24 responding pts, median DoR was 5.5 months (95% CI, 3.7-not estimable [NE]), and the 18-month estimated DoR rate was 41.0% (95% CI, 20.1-60.9). Median PFS was 5.8 months (95% CI, 3.8-8.1), and the 18-month estimated PFS rate was 32.3% (95% CI, 19.1-46.2). Median OS was NE, and the 18-month estimated OS rate was 78.3% (95% CI, 62.1-88.1). The efficacy outcomes by FLIPI risk category are presented in the Table. The median time on treatment was 7.6 months (range, 0.6-42.2), with 14 (29.2%) pts still receiving pirtobrutinib. The most frequent treatment-emergent adverse events (TEAEs), regardless of attribution, were diarrhea (29.2%, n=14), fatigue (25.0%, n=12), and nausea (22.9%, n=11). TEAEs of hemorrhage/hematoma (6.3%, n=3), hypertension (4.2%, n=2), and atrial fibrillation/flutter (2.1%, n=1) were infrequent. The most frequent grade ≥3 TEAEs were infection (18.8%, n=9) and neutropenia/neutrophil count decreased (14.6%, n=7). Only 1 (2.1%) pt had a treatment-related adverse event (rash) that led to pirtobrutinib discontinuation.

Conclusions: In this cohort of heavily pre-treated pts with R/R FL, pirtobrutinib showed potential efficacy and was well tolerated, including in pts with high risk FLIPI.