Pirtobrutinib Combo Cuts CLL Progression Risk 45% in Phase 3 Trial
LLY•In the Phase 3 BRUIN CLL-322 trial of pirtobrutinib plus venetoclax and rituximab in 639 relapsed/refractory CLL/SLL patients, the combination cut progression/death risk by 45% (HR 0.55; p=0.0001) over venetoclax and rituximab alone. Median PFS was not reached versus 39.7 months in the control arm at 27.3 months follow-up.
1. Trial Design and Patient Population
BRUIN CLL-322 enrolled 639 relapsed or refractory CLL/SLL patients, 79.8% of whom had prior covalent BTK inhibitor exposure. Participants were randomized 1:1 to receive pirtobrutinib plus venetoclax and rituximab or venetoclax and rituximab alone under a time-limited, two-year regimen.
2. Efficacy Outcomes
At a median follow-up of 27.3 months, addition of pirtobrutinib achieved a 45% reduction in progression or death risk (HR 0.55; 95% CI 0.40–0.75; p=0.0001). Median PFS was not reached with the triplet versus 39.7 months with venetoclax and rituximab, with consistent benefit across high-risk and BTK-pretreated subgroups.
3. Safety Profile
Overall Grade ≥3 adverse events were similar between arms (78.8% with pirtobrutinib vs 73.0% control). Low rates of atrial fibrillation/flutter (3.5% vs 2.6%), hypertension (12.0% vs 7.4%) and hemorrhage (14.2% vs 10.6%) were reported, with neutropenia at 50.3% vs 43.7% and tumor lysis syndrome at 0.9% vs 3.9%.
4. Regulatory and Next Steps
Lilly plans to submit BRUIN CLL-322 data to global regulatory authorities to expand pirtobrutinib’s label. The company is also evaluating the agent in multiple ongoing Phase 3 CLL/SLL studies to further support its role across treatment settings.
