KEY TAKEAWAYS
- The BRUIN phase 1 & 2 trial aimed to investigate the efficacy and safety of pirtobrutinib as a 1L therapy in BTK inhibitor-naïve patients with CLL/SLL.
- The key endpoints were to determine ORR, PFS & Safety.
- Researchers noticed that Pirtobrutinib shows promising efficacy and tolerability.
Early lines of therapy for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) often rely on targeted single-agent treatments like Bruton tyrosine kinase inhibitors (BTKi). Despite their efficacy, covalent BTKi have pharmacologic limitations such as low oral bioavailability and short half-life, potentially impacting BTK target coverage.
Pirtobrutinib, a non-covalent (reversible) BTKi, has shown promising efficacy and safety in relapsed or refractory (R/R) CLL/SLL, earning accelerated approval post multiple lines of therapy including BTKi and BCL2 inhibitors.
Dr. Toby Eyre and the team aimed to assess the efficacy and safety of pirtobrutinib as a first-line (1L) therapy in patients with BTKi-naïve CLL/SLL.
They performed an inclusive analysis of patients with R/R BTKi-naive CLL/SLL treated with pirtobrutinib. Key endpoints included overall response rate (ORR), assessed by both an independent review committee (IRC) and investigators per 2018 iwCLL criteria, progression-free survival (PFS), and safety outcomes.
About 35 patients with R/R BTKi-naïve CLL/SLL were treated with pirtobrutinib. The median age was 67 years (range, 38-81), with 18 patients (51.4%) male and 33 (94.3%) having an ECOG PS of 0-1. Patients had received a median of 2 prior therapies (range, 1-8) with 4 patients having only 1 prior therapy, 14 with 2 prior lines of therapy, and 17 with 3 or more prior lines of therapy. Predominantly including chemotherapy (100%), anti-CD20 antibody (97.1%), PI3K inhibitors (22.9%), and BCL-2 inhibitors (8.6%). Among those with available data, 20 out of 25 patients (80.0%) had unmutated IGHV, and 10 out of 27 (37.0%) had TP53 mutation and/or del(17p).
The median time on treatment was 28.8 months (mo), and the median time on study was 31.5 mo. The IRC-assessed ORR was 88.6% (95% CI, 73.3-96.8), with 1 patient (2.9%) achieving complete response (CR) and 30 (85.7%) partial responses (PR). The ORR including partial response with lymphocytosis (PR-L) was 91.4% (95% CI, 76.9-98.2), with 1 patient (2.9%) having PR-L. INV-assessed ORR was 85.7% (95%CI, 69.7-95.2), and including PR-L (n=3, 8.6%), was 94.3%(95%CI, 80.8-99.3).
The median follow-up was 28.1 months, and IRC-assessed median PFS was non-estimable (NE; 95% CI, 27.6-NE) with a 24-month PFS rate of 74.7% (95% CI, 55.7-86.5). INV-assessed median PFS was also NE (95%CI, 30.9-NE), and the 24-mo PFS rate was 81.8% (95%CI, 63.9-91.4). Common treatment-emergent adverse events (TEAE) included COVID-19 infection 19(n=16, 45.7%), neutropenia/neutrophil count decreased (n=15, 42.9%), and diarrhea (n=11, 31.4%).
Grade ≥3 TEAEs were predominantly infections ((n=16, 45.7%; n=9, 25.7% excluding COVID-19) and neutropenia/neutrophil count decreased (n=12, 34.3%). Grade ≥3 TEAEs of hypertension (8.6%, n=3), hemorrhage/hematoma (n=1, 2.9%), and a trial fibrillation/flutter (2.9%, n=1) were also observed. TEAEs led to pirtobrutinib dose reduction in 5 patients (14.3%) and discontinuation in 2 (5.7%). Two patients (5.7%) experienced fatal TEAEs due to COVID-19 infection, deemed unrelated to pirtobrutinib by investigators.
The study concluded that pirtobrutinib shows promising efficacy and good tolerability in patients with R/R BTKi-naïve CLL/SLL, with a low discontinuation rate. Ongoing phase 3 trials are assessing its use in patients with BTKi-naïve, including those in 1L treatment-naïve settings for CLL/SLL.
The trial was sponsored by Loxo Oncology, Inc.
Clinical Trial: https://clinicaltrials.gov/study/NCT03740529
Eyre T, Marańda E L, Roeker L, et al. (2024). “PIRTOBRUTINIB IN RELAPSED/REFRACTORY CLL/SLL: RESULTS FROMBTKI NAÏVE COHORT IN THE PHASE 1/2 BRUIN STUDY.” Presented at EHA 2024.
