Lilly: Jaypirca plus venetoclax‑rituximab lowers progression risk 45% in relapsed/refractory CLL/SLL

Study and context

BRUIN CLL-322 is a global, randomized, open‑label Phase 3 trial that enrolled 639 relapsed or refractory CLL/SLL patients, randomized 1:1 to pirtobrutinib plus venetoclax and rituximab (PVR, n=321) or venetoclax and rituximab alone (VR, n=318). The study reflects current practice: 79.8% of patients had prior covalent BTK inhibitor exposure. The data cutoff was Feb. 2, 2026. Results will be presented in a late‑breaking oral session at the 2026 EHA Annual Meeting.

Efficacy

The addition of pirtobrutinib (200 mg once daily in the trial) to a two‑year venetoclax+rituximab regimen met the primary endpoint of IRC‑assessed progression‑free survival, reducing risk of progression or death by 45% (HR=0.55; 95% CI 0.40–0.75; p=0.0001) at a median follow‑up of 27.3 months. Median PFS was not reached in the PVR arm versus 39.7 months in the VR arm. Benefits were consistent across prespecified subgroups, including prior covalent BTKi exposure and high‑risk genomic features. An exploratory analysis in second‑line patients after first‑line covalent BTKi showed HR=0.32 with 24‑month PFS rates of 88% versus 52%.

Safety and secondary endpoints

Overall safety was consistent with known profiles and showed little additive toxicity. Grade ≥3 AEs occurred in 78.8% (PVR) versus 73.0% (VR). Notable events: grade ≥3 neutropenia 50.3% vs 43.7%; tumor lysis syndrome 0.9% vs 3.9%; any‑grade atrial fibrillation/flutter 3.5% vs 2.6%. Time to next treatment favored PVR (HR=0.50; 95% CI 0.35–0.70). Overall survival data remain immature (HR=0.89; 95% CI 0.57–1.40).

Next steps

Lilly plans to submit BRUIN CLL-322 results to global regulatory authorities aiming to expand Jaypirca's label and is continuing Phase 3 evaluations in CLL/SLL.