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

• Published in: Blood 2024-11, Vol.144, p.886-886
• Main Authors: Sharman, Jeff P., Munir, Talha, Grosicki, Sebastian, Roeker, Lindsey, Burke, John M., Chen, Christine I, Grzasko, Norbert, Follows, George, Mátrai, Zoltán, Sanna, Alessandro, Yi, Shuhua, Feng, Ru, Hua, Vu Minh, Holodja, Jadwiga, Jurczak, Wojciech, Ritgen, Matthias, Qiu, Lu-Gui, Bosch, Francesc, Coombs, Catherine C., Bao, Katherine, Patel, Vishalkumar, Liu, Bin, Compte, Livia, Guntur, Ananya, Wang, Ying (Denise), Hill, Marisa, Leow, Ching Ching, Ghia, Paolo, Barr, Paul M
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-198147

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