Pirtobrutinib Triplet Prolongs Progression-Free Survival in Previously Treated CLL, Lancet Reports

The Lancet has published Phase 3 results showing that adding fixed-duration pirtobrutinib to venetoclax plus rituximab significantly improved progression-free survival in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma, compared with venetoclax plus rituximab alone.

The study, BRUIN CLL-322, enrolled 639 patients in an open-label, multicenter, randomized trial, assigning 321 to the pirtobrutinib-venetoclax-rituximab triplet and 318 to venetoclax plus rituximab. At a prespecified interim analysis with a Feb. 2, 2026, data cutoff, the triplet reduced the risk of disease progression or death by about 45%, with a hazard ratio of 0.547. At a median follow-up of 27.3 months, 24-month progression-free survival was 86.9% with the triplet versus 71.8% with the two-drug regimen. Median progression-free survival was not yet estimable in the triplet arm and was 39.7 months in the control arm.

The result matters because venetoclax plus rituximab is an established fixed-duration regimen for relapsed or refractory CLL, a blood cancer of mature white blood cells. Investigators and the journal summary described BRUIN CLL-322 as the first randomized Phase 3 evidence that a fixed-duration triplet built around pirtobrutinib can outperform that current standard in previously treated disease.

Pirtobrutinib, sold as Jaypirca, is a non-covalent BTK inhibitor, a type of targeted medicine designed to remain active in some patients whose disease has already been treated with earlier covalent BTK inhibitors. That was especially relevant in this trial: 79.8% of patients had previously received a covalent BTK inhibitor. According to the report, the progression-free survival benefit was consistent across prespecified high-risk subgroups, including patients with prior exposure to those drugs.

The triplet also produced deeper responses. The complete response rate was 31.8% with pirtobrutinib, venetoclax and rituximab, compared with 23.3% for venetoclax plus rituximab. Among evaluable end-of-treatment samples, undetectable minimal residual disease at the MRD4 level — meaning no disease detected below a standard threshold in blood or marrow testing — was 86.3% with the triplet and 60.7% with the control regimen.

Safety was described as broadly similar between groups, with no new safety signals reported. Grade 3 or higher treatment-emergent adverse events occurred in 78.8% of patients in the triplet arm and 73% in the control arm. The most common adverse event was neutropenia, a drop in infection-fighting white blood cells: 60.4% with the triplet versus 54% with venetoclax plus rituximab. Grade 3 or higher neutropenia occurred in about 49.7% and 43.7%, respectively. Discontinuations due to treatment-related adverse events were low and similar, at 5.4% with the triplet and 5.1% with the control treatment. Overall survival data were not yet mature at the interim look.

The results were previously presented in a late-breaking oral session at the European Hematology Association annual meeting in Stockholm on June 14. Matthew S. Davids, the study’s lead author and presenter, said in a Lilly press release that the findings “show that the addition of pirtobrutinib as part of a time-limited regimen further enhanced an already effective treatment and extended the duration of remission for patients with previously treated CLL. Importantly, the study provides the first robust evidence for such an approach in patients who received a prior BTK inhibitor.” Lilly, which sponsors the trial, has said it plans to submit the results to regulators globally to seek a label expansion for pirtobrutinib.