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BRUIN CLL-322

A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Phase 3N = 639NCT04965493

Population
Previously treated CLL or SLL (at least one prior line, which could include a covalent BTK inhibitor); 510 of 639 patients (80%) had previous covalent BTK inhibitor exposure. Patients with previous non-covalent BTK inhibitor, venetoclax or another BCL2 inhibitor were excluded.
Design
Open-label randomised phase 3 at 152 sites in 22 countries: pirtobrutinib plus venetoclax-rituximab (pirtobrutinib for 28 cycles with a three-cycle pirtobrutinib-rituximab lead-in) versus venetoclax-rituximab (venetoclax for 25 cycles, rituximab for six). Results are from a prespecified interim analysis (data cutoff 2 February 2026). ClinicalTrials.gov lists 600 as estimated enrolment; the paper reports 639 randomised, and the paper's number is used.
Primary endpoint
PFS
Arms
  • Pirtobrutinib-venetoclax-rituximab (experimental, n = 321): Pirtobrutinib (28 cycles) plus venetoclax (25 cycles) and rituximab (6 cycles)
  • Venetoclax-rituximab (control, n = 318): Venetoclax (25 cycles) plus rituximab (6 cycles)
People
Davids MS
PFSHR 0.547 (95% CI 0.400–0.748)Δ 24-month PFS+15 points
Show the numbers
Results reported for BRUIN CLL-322
EndpointAnalysisPirtobrutinib-venetoclax-rituximabVenetoclax-rituximabEffect
PFSIntention-to-treat population (639 randomised)interimmedian follow-up 27.3 monthsDavids 202687% at 2 y (82.3–90.4%)median 39.7 months; 72% at 2 y (65.7–77.0%)HR 0.547 (95% CI 0.400–0.748)P=0.0001Progression-free survival assessed by a masked independent review committee at a prespecified interim analysis. Median not reached with pirtobrutinib plus venetoclax-rituximab; 39.7 months (IQR 21.5 to 50.0) with venetoclax-rituximab; the interquartile range is labelled in the full text, the abstract gives the bracket unlabelled.
Results reported for BRUIN CLL-322
EndpointAnalysisPirtobrutinib-venetoclax-rituximabVenetoclax-rituximabEffect
PFSIntention-to-treat population (639 randomised)interimmedian follow-up 27.3 monthsDavids 202687% at 2 y (82.3–90.4%)median 39.7 months; 72% at 2 y (65.7–77.0%)HR 0.547 (95% CI 0.400–0.748)P=0.0001Progression-free survival assessed by a masked independent review committee at a prespecified interim analysis. Median not reached with pirtobrutinib plus venetoclax-rituximab; 39.7 months (IQR 21.5 to 50.0) with venetoclax-rituximab; the interquartile range is labelled in the full text, the abstract gives the bracket unlabelled.
Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.
PFS0.512◀ experimentalcontrol ▶
Data table
EndpointHR95% CI
PFS0.5470.4–0.748
Illustrative — modelled from reported values, not trial data. PFS, interim.
0%25%50%75%100%020406080Months (modelled)
  • Venetoclax-rituximab (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsVenetoclax-rituximab
0100.0%
2564.6%
5041.8%
7427.5%
9917.8%
Primary publication: Davids MS, Eyre TA, Woyach JA, Roeker LE, Ferrajoli A, Wang Y, et al. Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (BRUIN CLL-322): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet. 2026;408(10553):453-470. PubMedDOI

Appears in

Sources

  1. Davids MS, Eyre TA, Woyach JA, Roeker LE, Ferrajoli A, Wang Y, et al. Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (BRUIN CLL-322): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet. 2026;408(10553):453-470.

    PubMedDOI