BRUIN CLL-321: Randomized Phase III Trial of Pirtobrutinib Versus Idelalisib Plus Rituximab (IdelaR) or Bendamustine Plus Rituximab (BR) in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background: Patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who relapse after treatment with covalent Bruton tyrosine kinase inhibitors (cBTKi) have limited effective treatment options. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that has shown promising safety and efficacy in pts with CLL/SLL after cBTKi therapy. Here we report results from the first randomized phase III study among CLL/SLL pts with relapsed/refractory disease who were all previously treated with cBTKi comparing pirtobrutinib versus investigators choice (IC) of IdelaR or BR (BRUIN CLL-321, NCT04666038). Methods: Eligible CLL/SLL pts previously treated with cBTKi were randomized 1:1 to receive pirtobrutinib monotherapy (200mg QD) or IC of IdelaR or BR and stratified by prior use of venetoclax and del(17p) status. The primary endpoint was progression free survival (PFS) assessed by independent review committee (IRC) per iwCLL2018 criteria. Secondary endpoints included investigator (INV) assessed PFS, event-free survival (EFS), time to next treatment (TTNT), overall survival (OS), and safety. Efficacy analyses were based on the intent to treat population. Crossover to pirtobrutinib arm was allowed after IRC confirmed disease progression (PD). The primary endpoint of PFS was met at primary analysis (29 Aug 2023 data cut). An updated analysis using a 09 Feb 2024 data cut is reported here. Further updates will be presented at the meeting. Results: 238 pts from 23 countries were randomized to receive pirtobrutinib (n=119) or IC (n=119) of IdelaR (n=82) or BR (n=37). Median age was 67 (range, 42-90). Pts across both arms received a median of 3 prior lines of therapy (range, 1-13), all received prior cBTKi and half (50.4%) with prior venetoclax treatment. Pts with evaluable samples in pirtobrutinib vs. IC arm, respectively, had unmutated IGHV (92.8% vs. 79.6%); complex karyotype (71.6% vs. 58.7%); del(17p) (46.2% vs. 44.5%). Reason for discontinuation of prior cBTKi included PD (70.6% vs. 72.3%) and toxicity (16.8% vs. 17.6%). At the primary PFS analysis with a median follow-up of 6.1 months (mo; 95%CI, 4.2-9.5), IRC-assessed PFS was significantly improved with pirtobrutinib compared to IC (HR, 0.58; 95%CI 0.38-0.89; p=0.01). At the updated analysis with a median follow-up of 11.6 mo (95%CI, 7.9-17.4), IRC assessed PFS HR was 0.55 (95%CI, 0.38-0.78; p=0.0007). INV-assessed PFS also showed benefit, with an HR of 0.42 (95%CI, 0.29-0.62; p<0.0001). Pirtobrutinib continued to show benefit in IRC-assessed PFS across subgroups compared to IC, including pts with prior venetoclax treatment (HR, 0.54 [95%CI, 0.33-0.86]), with complex karyotype (HR, 0.34 [95%CI, 0.21-0.56]), and with TP53 mutation and/or del(17p) (HR, 0.52 [95%CI, 0.33-0.84]). EFS was superior in pts on pirtobrutinib arm (HR, 0.35 [95%CI, 0.25-0.50]) compared to IC. TTNT was also significantly better in pirtobrutinib arm (HR, 0.38 [95%CI, 0.25-0.56]). OS data are immature, with median OS not reached in either arm. The most common treatment-emergent adverse events (TEAE) occurring in ≥15% of pts in pirtobrutinib arm were anemia (20.7%), pneumonia (19.8%), neutropenia (16.4%), and diarrhea (15.5%). The most common TEAE in IC arm was diarrhea (29.4%), pyrexia (25.7%), nausea (20.2%), COVID-19 (18.3%), fatigue (18.3%), neutrophil count decreased (17.4%), and ALT increased (17.4%). Grade ≥3 TEAE (55.2% vs. 71.6%) were lower in pirtobrutinib vs. IC arm. Treatment discontinuation due to AE, regardless of relatedness to treatment, occurred in 17 (14.7%) pts in pirtobrutinib arm and 35 (32.1%) in IC arm. Discontinuation due to treatment-related AE (5.2% vs. 18.3%), and dose reductions due to AE (7.8% vs. 28.4%) were lower with pirtobrutinib than IC, respectively. Any grade atrial fibrillation/flutter occurred in 3 (2.6%) patients in pirtobrutinib arm and 1 (0.9%) patient in IC arm. Any grade hypertension occurred in 7 (6.0%) and 4 (3.7%) pts in pirtobrutinib and IC arms, respectively. Grade >3 hemorrhage was infrequent, occurring in 1 (0.9%) patient each in both pirtobrutinib and IC arms. Summary/Conclusion: BRUIN CLL-321 is the first randomized study conducted exclusively in cBTKi pretreated CLL/SLL pts. In this heavily pretreated patient population with poor prognosis, pirtobrutinib treatment led to a significant improvement in PFS compared to IC, along with a more favorable safety profile.

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