Pirtobrutinib Combo Boosts PFS in Previously Treated CLL/SLL

Fixed-duration pirtobrutinib (Jaypirca) plus venetoclax (Venclexta) and rituximab (Rituxan; PVR) significantly improved progression-free survival (PFS) vs venetoclax/rituximab alone (VR) in patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase 3 BRUIN CLL-322 trial (NCT04965493) published in The Lancet.¹

What were the efficacy findings of BRUIN CLL-322?

At a median follow-up of 27.3 months (IQR, 25.5-29.9), PVR significantly improved PFS, as assessed by a masked independent review committee (IRC), compared with VR (HR, 0.547; 95% CI, 0.400-0.748; P = .0001). The 24-month PFS rate was 86.9% (95% CI, 82.3%-90.4%) in the PVR group vs 71.8% (95% CI, 65.7%-77.0%) in the VR group, and median PFS was not reached (IQR, 31.7-not estimable) with PVR vs 39.7 months (IQR, 21.5-50.0) with VR. The benefit was consistent across prespecified subgroups, including patients with previous exposure to covalent Bruton tyrosine kinase (BTK) inhibitors.

The IRC-assessed overall response rate (ORR) was 88.5% (95% CI, 84.5%-91.8%; n = 284/321 patients) with PVR vs 83.3% (95% CI, 78.8%-87.3%; n = 265/318 patients) with VR (P = .062). A complete response (CR) or CR with incomplete bone marrow recovery was reached by 102 patients (32%) in the PVR group vs 74 (23%) in the VR group. Among patients with evaluable samples at the end of treatment (n = 117 per group), rates of undetectable minimal residual disease (uMRD) were higher with PVR than VR (86% vs 61%; P <.0001).

Event-free survival was longer with PVR (HR, 0.692; 95% CI, 0.533-0.900; P = .0056). Overall survival (OS) interim data were immature (HR, 0.891; 95% CI, 0.568-1.398), with the median OS not reached in either group.

What were the safety findings of BRUIN CLL-322?

The most frequent any-grade treatment-emergent adverse event (AE) in both groups was diarrhea, reported in 106 of 316 patients (34%) in the PVR group and 110 of 311 patients (35%) in the VR group. Grade 3 or higher AEs were similar between groups (79%; n = 249/316 vs 73%; n = 227/311). The rate of grade 3 or higher tumor lysis syndrome was lower with PVR (1%; n = 3/316) than with VR (4%; n = 12/311), and any-grade atrial fibrillation or flutter was low in both groups (3% each). Treatment discontinuation owing to related AEs occurred in 5% of patients in each group. Five treatment-related deaths occurred: 1 in the PVR group and 4 in the VR group.

"To our knowledge, these results represent the first randomized phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory [CLL], supporting PVR as a potential new standard of care," lead author Matthew S. Davids, MD, MMSc, director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute, wrote in the publication with study coinvestigators.¹ “Further analysis of [OS] is planned to assess long-term survival benefit. These results support PVR as an effective, well tolerated, fixed-duration treatment option for previously treated [CLL], including in patients with previous exposure to covalent BTK inhibitors.”

How was BRUIN CLL-322 designed?

BRUIN CLL-322 was an open-label, multicenter, randomized, controlled, phase 3 trial conducted at 152 sites across 22 countries. Between October 13, 2021, and October 28, 2024, 639 patients were randomly assigned 1:1 to PVR (n = 321) or VR (n = 318), stratified by del(17p) status and previous covalent BTK inhibitor exposure. Both groups received oral venetoclax for 25 cycles and intravenous rituximab for 6 cycles; the PVR group also received oral pirtobrutinib at 200 mg orally once daily for 28 cycles, with a 3-cycle pirtobrutinib/rituximab lead-in before venetoclax initiation.

Eligible patients were 18 years or older with previously treated CLL/SLL; those who had received a prior non-covalent BTK inhibitor, venetoclax, or another BCL2 inhibitor were excluded. The median age was 68.0 years (IQR, 60.0-74.0), and 80% of patients had previous covalent BTK inhibitor exposure.

For this prespecified interim analysis, the primary end point was PFS in the intention-to-treat population, assessed by masked IRC per 2018 International Workshop on Chronic Lymphocytic Leukemia guidelines. The key secondary end point was OS; other prespecified secondary end points included investigator-assessed PFS, time to next treatment, event-free survival, ORR, and safety.

The authors noted that venetoclax/rituximab became a fixed-duration standard of care based on the phase 3 MURANO trial (NCT02005471).² Additionally, the non-covalent BTK inhibitor pirtobrutinib was previously evaluated as continuous monotherapy in the phase 3 BRUIN CLL-321 trial (NCT04666038).³

References

1. Davids MS, Eyre TA, Woyach JA, 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. Published online July 9, 2026. doi:10.1016/S0140-6736(26)01204-3
2. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976
3. Sharman JP, Munir T, Grosicki S, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-2549. doi:10.1200/JCO-25-00166. Erratum in: J Clin Oncol. 2025;43(23):2658. doi:10.1200/JCO-25-01356