Patient-reported outcomes in BRUIN CLL-321: A randomized phase 3 trial comparing pirtobrutinib to investigators choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma in the post-cBTKi setting

Introdcution The phase 3, randomized trial BRUIN CLL-321 assessed the safety and efficacy of pirtobrutinib versus investigators choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) previously treated with a covalent BTK inhibitor. BRUIN CLL-321 showed significantly improved progression-free survival with pirtobrutinib compared to IdealR/BR. We report secondary endpoints including time to worsening (TTW) of CLL/SLL-related symptoms and physical function (PF). Materials and Methods Patients with relapsed/refractory CLL/SLL who received at least one prior cBTKi were enrolled in BRUIN CLL-321. Exploratory endpoints were evaluated using mixed models for repeated measures analysis for within- and between-group differences. Patient-reported outcomes (PROs) were collected every 4 weeks during study treatment through week 25 on both arms. TTW was evaluated using log rank test and Cox proportional hazards model. The statistical testing of PRO endpoints was not type-1 error controlled and thus descriptive in nature. Results A total of 119 patients were randomized to each treatment arm ( N = 238). Median TTW in CLL/SLL-related symptoms (HR,0.972 [95%CI, 0.461–2.048; p = 0.89) and PF (HR, 0.590 [95%CI, 0.262–1.326]; p = 0.33) was not reached in either treatment arm. Pirtobrutinib demonstrated clinically meaningful improvements from baseline in CLL/SLL-related symptoms, PF, and fatigue at all post-baseline assessments (least squares [LS] means change ranged from −7.0 to −11.8, +5.4 to +8.9, and − 7.0 to −12.7, respectively). Comparing between groups, CLL/SLL-related symptoms were clinically meaningfully lower in the pirtobrutinib group versus IdelaR/BR at Week 9 (LSM d ,-7.3 [standard error (SE), 2.2]), Week 13 (LSM d ,-6.7 [SE, 2.3]), Week 17 (LSM d ,-4.6 [SE, 2.3]), and Week 21 (LSM d ,-7.0 [SE, 2.3]). Patients receiving pirtobrutinib reported better PF versus IdelaR/BR at Weeks 13 (LSM d ,5.6 [SE, 2.4]) and 21 (LSM d ,5.9 [SE, 2.5]). Patients receiving pirtobrutinib also reported clinically meaningful lower fatigue versus IdelaR/BR at Week 9 (LSM d ,-9.0 [SE, 2.9]), Week 13 (LSM d ,-6.7 [SE, 3.0]), and Week 21 (LSM d ,-6.9 [SE, 3.1]). Discussion These analyses demonstrate clinically meaningful improvements for pirtobrutinib at all post-baseline assessments for CLL/SLL-related symptoms, PF, and fatigue. Consistent benefit was seen in CLL/SLL-related symptoms, PF, and fatigue with pirtobrutinib versus IdelaR/BR, with most PRO assessments meeting clinically meaningful differences between groups.