Background
Open-label, multicentre, randomised phase 3 trial (152 sites, 22 countries) in adults with previously treated CLL/SLL (≥1 prior line, could include a covalent BTK inhibitor). Prior non-covalent BTKi, venetoclax, or other BCL2 inhibitor excluded. Venetoclax–rituximab (VR) is the fixed-duration standard of care after a covalent BTKi; pirtobrutinib is a non-covalent BTKi. N=639. Data cutoff Feb 2, 2026 (prespecified interim analysis).
Results
Interventions and follow up: Arm A (PVR): pirtobrutinib PO for 28 cycles (with a 3-cycle pirtobrutinib–rituximab lead-in) + venetoclax PO 25 cycles + rituximab IV 6 cycles
Arm B (VR): venetoclax PO 25 cycles + rituximab IV 6 cycles
Primary endpoint: IRC-assessed progression-free survival (ITT, 2018 iwCLL criteria)
mFollow up: 27.3 months
Results: PFS (IRC): HR 0.547 (95% CI 0.400–0.748), P=.0001
24-mo PFS: 87% (PVR) vs 72% (VR)
Median PFS: not reached vs 39.7 months
OS: NR
Arm B (VR): venetoclax PO 25 cycles + rituximab IV 6 cycles
Primary endpoint: IRC-assessed progression-free survival (ITT, 2018 iwCLL criteria)
mFollow up: 27.3 months
Results: PFS (IRC): HR 0.547 (95% CI 0.400–0.748), P=.0001
24-mo PFS: 87% (PVR) vs 72% (VR)
Median PFS: not reached vs 39.7 months
OS: NR
Adverse events
Grade ≥3 (any): 79% vs 73%
Diarrhoea (any grade): 34% vs 35%
Tumour lysis syndrome G≥3: 1% vs 4%
Atrial fibrillation/flutter (any): 3% vs 3%
Discontinuation (drug-related AE): 5% vs 5%
Treatment-related deaths: 1 vs 4
Diarrhoea (any grade): 34% vs 35%
Tumour lysis syndrome G≥3: 1% vs 4%
Atrial fibrillation/flutter (any): 3% vs 3%
Discontinuation (drug-related AE): 5% vs 5%
Treatment-related deaths: 1 vs 4
Conclusions
Adding pirtobrutinib to fixed-duration venetoclax–rituximab significantly improved PFS versus VR in relapsed/refractory CLL/SLL, with benefit preserved in patients previously exposed to covalent BTK inhibitors and no new safety signals. This is the first randomised phase 3 evidence for a novel fixed-duration regimen against the VR standard, supporting PVR as a potential new standard of care.
Key Limitations
Open-label design; prespecified interim analysis with short median follow-up (27.3 mo) and median PFS not yet reached in the experimental arm; overall survival immature and not reported; adds a third agent (cost/complexity) to a fixed-duration backbone; patients with prior venetoclax/BCL2i or non-covalent BTKi were excluded, limiting applicability to venetoclax-exposed relapse.
Clinical Context
Addresses relapsed/refractory CLL/SLL after covalent BTKi, where fixed-duration VR is a current standard. Pirtobrutinib (Jaypirca) is already FDA-approved as monotherapy for CLL/SLL after ≥2 prior lines including a BTKi and a BCL2 inhibitor; it is not yet approved in this fixed-duration triplet. NCCN lists pirtobrutinib among preferred later-line options; these data position PVR as a possible new fixed-duration standard pending OS and regulatory review.