Adding the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) to fixed-duration venetoclax (Venclexta) plus rituximab (Rituxan) significantly prolonged progression-free survival (PFS) compared with venetoclax/rituximab (VR) alone in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a prespecified interim analysis of the phase 3 BRUIN CLL-322 trial (NCT04965493). The findings were presented by Matthew S. Davids, MD, MMSc, of Dana-Farber Cancer Institute, during an oral session at the 2026 European Hematology Association (EHA) Congress.1
BRUIN CLL-322 is the first randomized phase 3 trial to evaluate a fixed-duration targeted therapy in a CLL population with prior covalent BTK inhibitor (cBTKi) exposure, an increasingly common clinical scenario for which data have been limited. Pirtobrutinib is the first and only approved noncovalent BTK inhibitor and has demonstrated activity as continuous monotherapy across CLL settings, including after cBTKi treatment.
Investigators randomly assigned 639 patients in a 1:1 ratio to fixed-duration pirtobrutinib plus venetoclax and rituximab (PVR; n = 321) or VR (n = 318), stratified by del(17p) status and prior cBTKi experience. Eligible patients had relapsed or refractory CLL or SLL requiring treatment per iwCLL 2018 criteria and at least 1 prior line of therapy; prior noncovalent BTK inhibitor or venetoclax exposure was not permitted, and enrollment of cBTKi-naive patients was capped at approximately 20%. The VR regimen was administered for 25 cycles and the PVR regimen for 28 cycles with a pirtobrutinib lead-in; all therapy was time-limited, and no crossover was permitted. The primary end point was PFS assessed by an independent review committee (IRC), and the data cutoff was February 2, 2026.
The median age was 68.0 years (range, 32-85) in the PVR arm and 67.0 years (range, 37-87) in the VR arm, and most patients were male (67.3% and 70.1%, respectively). Patients had received a median of 2 prior lines of therapy, and approximately 80% had prior cBTKi exposure—most commonly ibrutinib (Imbruvica)—with more than half having discontinued their prior cBTKi because of progressive disease. The population carried substantial high-risk features, including unmutated IGHV in 63.2% of the PVR arm and 70.8% of the VR arm, and TP53 mutations and/or del(17p) in 39.3% and 41.5%, respectively. Bulky disease of 5 cm or greater was present in roughly one-third of patients.
At a median follow-up of 27.3 months, PVR demonstrated superior PFS by IRC evaluation, with a 24-month PFS rate of 86.9% (95% CI, 82.3%-90.4%) vs 71.8% (95% CI, 65.7%-77.0%) with VR. The hazard ratio for progression or death was 0.547 (95% CI, 0.400-0.748; stratified log-rank P =.0001), corresponding to a 45% reduction in risk. Median PFS was not estimable (NE; 95% CI, 43.3-NE) with PVR and was 39.7 months (95% CI, 35.9-NE) with VR. Sixteen Richter transformation events occurred in the VR arm compared with 8 in the PVR arm.
The PFS benefit was consistent across prespecified subgroups. Among patients with prior cBTKi exposure, the hazard ratio was 0.509 (95% CI, 0.351-0.738; P = .0003); among those who had discontinued a prior cBTKi because of progressive disease, it was 0.444 (95% CI, 0.293-0.673; P <.0001); and among patients whose only prior therapy was a cBTKi they had progressed on, the hazard ratio was 0.323 (95% CI, 0.144-0.728; P = .0038), with a 24-month PFS rate of 88.4% (95% CI, 75.7%-94.6%) vs 51.6% (95% CI, 34.7%-66.2%) with VR. Time to next treatment also favored PVR (HR, 0.498; 95% CI, 0.352-0.704; P <.0001), while overall survival data were immature at this analysis.
The overall response rate was 88.5% (95% CI, 84.5%-91.8%) with PVR and 83.3% (95% CI, 78.8%-87.3%) with VR (P = .0618), with complete response rates of 31.8% and 23.3%, respectively. Among patients with evaluable end-of-treatment samples, undetectable minimal residual disease (MRD) at a sensitivity of 10⁻⁴ in peripheral blood was achieved in 86.3% of PVR patients vs 60.7% of VR patients (P <.0001), and the advantage was maintained at greater sequencing depths.
Nearly all patients experienced at least 1 treatment-emergent adverse event (TEAE). Grade 3 or higher neutropenia was the most common event, occurring in 49.7% of PVR patients and 43.7% of VR patients, and grade 3 or higher infections were reported in 33.9% and 23.2%, respectively. Rates of atrial fibrillation or flutter were not increased with PVR, and grade 3 or higher bleeding was similar between arms, consistent with pirtobrutinib’s established cardiovascular profile. Hypertension was slightly more frequent with PVR (12.0% vs 7.4%). Treatment-related TEAEs led to discontinuation in 5.4% of PVR patients and 5.1% of VR patients, and grade 5 treatment-related events occurred in 0.3% and 1.3%, respectively.
Davids concluded that fixed-duration PVR was generally well tolerated, with a safety profile consistent with the individual agents and no new safety signals, and that the results support PVR as a potential new standard-of-care option for patients with previously treated CLL. He noted that the 24-month PFS rate of 71.8% in the VR control arm was notably lower than the 86.9% rate reported in the chemoimmunotherapy-treated MURANO (NCT02005471) population, suggesting that the post-cBTKi patients enrolled in BRUIN CLL-322 represented a particularly high-risk group.
“This [study] suggests very good likelihood that we’ll see prolonged remissions, especially in those [patients who received] PVR, and [it] gives me good confidence that we can use that regimen and expect a very long treatment-free interval, even in patients who have high-risk CLL,” Davids said in a conversation with CancerNetwork® at the meeting
Disclosures: The study was sponsored by Eli Lilly and Company. A full list of investigators and author disclosures is available with the original presentation.
Reference
Davids MS, Eyre TA, Woyach JA, et al. Fixed-duration pirtobrutinib plus venetoclax-rituximab versus venetoclax-rituximab for patients with previously treated CLL/SLL: a phase 3, randomized trial (BRUIN CLL-322). Presented at: 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract LB5001.
