Pirtobrutinib, a Highly Selective, Non-Covalent (Reversible) BTK Inhibitor in Relapsed / Refractory Marginal Zone Lymphoma: Results from Phase 1/2 BRUIN Study
Authors: Patel Krish , Vose Julie M. , Nasta Sunita D. , Brown Jennifer R. , Maddocks Kami J. , Woyach Jennifer A. , Shah Nirav N. , Fakhri Bita , Tessoulin Benoit , Ma Shuo , Jagadeesh Deepa , Lech-Maranda Ewa , Coombs Catherine C. , Patel Manish , Rhodes Joanna M. , Ujjani Chaitra S , Hoffmann Marc S. , Cheah Chan Y , Munir Talha , Lewis David , Scarfo Lydia , Eyre Toby A. , Alencar Alvaro J. , Cohen Jonathon B. , Zelenetz Andrew D. , Tsai Donald E. , Li Mei , Bian Faith , Abada Paolo , Zinzani Pier Luigi 
Published: December 2023

Background: Marginal zone lymphoma (MZL) is an indolent lymphoma that is typically treated with chemoimmunotherapy, but often requires sequential therapy. Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) are increasingly being used in the relapsed or refractory (R/R) setting, but options for pts with MZL after cBTKi therapy may be limited. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable once daily oral pharmacology that enables continuous BTK inhibition throughout the dosing interval, regardless of intrinsic rate of BTK turnover. Pirtobrutinib has demonstrated promising efficacy and tolerability in pts with poor-prognosis B-cell malignancies following prior therapy, including prior cBTKi. Pirtobrutinib is approved in the USA to treat R/R mantle cell lymphoma after at least two lines of systemic therapy including prior BTKi treatment. Here we report the safety and efficacy of pirtobrutinib in pts with MZL from the BRUIN study (NCT03740529).

Methods: Pts with previously treated B-cell malignancies, including MZL, were eligible for pirtobrutinib monotherapy treatment in either the dose escalation or expansion portion of the multicenter, phase 1/2 BRUIN study. MZL diagnosis required local pathologic review of an adequate biopsy. Endpoints include overall response rate (ORR) assessed by investigator per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A 05 May 2023 data cut was used.

Results: Among the 36 pts with MZL, 34 (94%) received the recommended phase 2 dose of pirtobrutinib, 200mg once daily.Pts had a median age of 68 (range 22-83), a majority were female (56%, n=20), and median prior lines of systemic therapy were 3 (range 1-10). Pts had nodal (47%, n=17), splenic (36%, n=13), and extranodal (17%, n=6) MZL subtypes. Most pts had Ann Arbor stage III/IV disease (81%, n=29). Most pts were in high risk MALT-IPI group (53%, n=19), 10 (28%) were intermediate, 1 (3%) was low, and missing in 6 (17%) pts. Baseline LDH was elevated in 15 (42%) pts and hemoglobin was &lt;12 g/dL in 29 (81%) pts. All 36 MZL pts were previously treated with an anti-CD20 antibody, and 31 (86%) pts had received prior chemotherapy. Of the 26 pts (72%) with MZL who received a prior cBTKi, 20 (77%) pts discontinued due to progressive disease (PD) and 6 (23%) discontinued due to toxicity/other. Median time on treatment was 9 months (range 1.1-40.8), with 15 (47.1%) pts still receiving pirtobrutinib.

The ORR of the MZL cohort was 50% (95% confidence interval [CI], 32.9- 67.1), including 1 (2.8%) complete response, 17 (47.2%) partial responses ( Figure). There were 15 (41.7%) pts with stable disease. The ORR in pts with nodal, splenic, and extranodal MZL were 58.8% (95%CI, 32.9-81.6), 30.8% (95%CI, 9.1-61.4), and 66.7% (95%CI, 22.3-95.7), respectively. The ORR for MZL pts with prior cBTKi therapy was 46.2% (95%CI, 26.6-66.6). With a median follow-up time of 17.6 months, median DOR was 12.7 months (95%CI, 5.6-non-estimable [NE]). Median PFS was 16.5 months (95%CI, 7.43-22.1) with a median follow up of 15.8 months. With a median follow up of 21.5 months, the median OS was NE (95%CI, 27.6-NE) and the 24-mo OS rate was 77.5% (95%CI, 56.3-89.3).

In the MZL cohort, the most frequent treatment-emergent adverse events (TEAE) of any grade regardless of attribution were diarrhea (36.1%, n=13), fatigue (33.3%, n=12), and contusion (30.6%, n=11). Grade ≥3 hemorrhage/hematoma was not observed, and any grade hypertension (5.6%, n=2) was infrequent. No atrial fibrillation/flutter was observed. The most frequent grade ≥3 TEAE was neutropenia/neutrophil count decreased (27.8%, n=10) and anemia (13.9%, n=5). Treatment-related AE led to dose reductions in 4 pts (11.1%) and pirtobrutinib discontinuation in 2 (5.6%) pts (diarrhea and platelet count decreased/neutropenia). No fatal TEAEs were observed.

Conclusions: In this cohort of heavily pre-treated R/R MZL pts, pirtobrutinib showed preliminary efficacy and was well tolerated with low rates of discontinuation.Pirtobrutinib appears to be a promising therapeutic option after cBTKi treatment in R/R MZL pts.