Fixed-duration pirtobrutinib (Jaypirca) plus venetoclax (Venclexta) and rituximab (Rituxan; PVR) demonstrated superior progression-free survival (PFS) outcomes compared with fixed-duration venetoclax and rituximab (VR) in patients with relapsed or refractory
Findings showed that at a median follow-up of 27.3 months, the median PFS was not estimable (NE; 95% CI, 43.3-NE) with PVR (n = 321) vs 39.7 months (95% CI, 35.9-NE) with VR (n = 318) per independent review committee (IRC) assessment (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 arm compared with 71.8% (95% CI, 65.7%-77.0%) in the VR arm. “We believe that these results establish PVR as a potential new standard of care and option for patients with previously treated CLL,” lead study author Matthew S. Davids, MD, MMSc, of Dana-Farber Cancer Institute in Boston, Massachusetts, said in a presentation of the data.
Previously, the
Building on prior efficacy and safety data with pirtobrutinib as monotherapy, BRUIN CLL-322 sought to evaluate its addition to VR in the relapsed/refractory setting.1 The randomized, open-label, global, multicenter phase 3 trial enrolled patients 18 years or older with CLL or SLL requiring treatment per International Workshop on CLL 2018 criteria. Patients needed to have relapsed/refractory disease following at least 1 prior line of therapy. Notably, prior treatment with a covalent BTK inhibitor was permitted but not required, and investigators capped the enrollment of covalent BTK inhibitor–naive patients at approximately 20% of the total population. Other key inclusion criteria comprised known 17p deletion (del[17p]) status by fluorescence in situ hybridization and an ECOG performance status of 2 or lower. Patients with prior noncovalent BTK inhibitor or venetoclax/BCL2 inhibitor exposure were excluded.
A total of 639 patients were randomly assigned 1:1 to receive fixed-duration PVR (comprising pirtobrutinib at 200 mg daily for 28 cycles; venetoclax at 400 mg daily for cycles 5 through 28, with weekly ramp-up in cycles 4 and 5 to reach the target dose; and rituximab at 375 mg/m2 on cycle 1, day 1 and 500 mg/m2 on day 1 of cycles 2 through 6) or fixed-duration VR (comprising venetoclax at 400 mg daily for cycles 2 through 25, with ramp-up in cycle 1 to reach the target dose, and rituximab at 375 mg/m2 on cycle 2, day 1 and 500 mg/m2 on day 1 of cycles 2 through 7). Stratification factors included del(17p) status (positive vs negative) and prior covalent BTK inhibitor exposure (discontinuation due to progressive disease vs discontinuation for other reasons vs no prior exposure).
The primary end point was IRC-assessed PFS; secondary end points included overall survival, investigator-assessed PFS, time to next treatment (TTNT), overall response rate (ORR), and safety. Measurable residual disease (MRD) assessed by clonoSEQ in peripheral blood was an exploratory end point. The data cutoff was February 2, 2026.
Baseline characteristics were well-balanced between the 2 arms. 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. Europe was the most common region for enrollment in both arms (46.4% for PVR vs 44.3% for VR), followed by North America (32.4% vs 34.6%). Most patients had an ECOG performance status of 0 or 1 (93.5% vs 94.7%) and had stage 0 to II disease (64.2% vs 61.4%). Bulky disease was reported in both groups (36.1% vs 33.6%), and high-risk features included unmutated IGHV (63.2% vs 70.8%), complex karyotype with at least 3 abnormalities (26.2% vs 36.8%), del(17p) (20.6% vs 22.3%), TP53 mutation (33.0% vs 35.2%), and TP53 mutation and/or del(17p) (39.3% vs 41.5%). The median duration of disease was 8.6 years (range, 0.4-33.7) in the PVR arm vs 8.4 years (range, 0.2-27.9) in the VR arm.
Patients had received a median of 2 prior lines of systemic therapy (range, 1-7) in the PVR arm and 2 prior lines (range, 1-9) in the VR arm. Prior treatments included a covalent BTK inhibitor (79.8% for PVR vs 79.9% for VR), an anti-CD20 antibody (68.2% vs 66.0%), chemotherapy (66.4% vs 65.4%), and other (23.4% vs 23.9%). In the PVR arm, prior covalent BTK inhibitor experience included discontinuation due to progressive disease in 56.4% of patients, discontinuation due to intolerance in 13.7% of patients, discontinuation for other reasons in 9.7% of patients, and no prior covalent BTK inhibitor exposure in 20.2% of patients. These respective rates in the VR arm were 56.9%, 11.0%, 11.9%, and 20.1%.
The IRC-assessed ORR was 88.5% (95% CI, 84.5%-91.8%) with PVR vs 83.3% (95% CI, 78.8%-87.3%) with VR (P = .0618). The complete response rate was higher with PVR at 31.8% vs 23.3% with VR.
PVR also reduced the risk of requiring subsequent therapy vs VR (HR, 0.498; 95% CI, 0.352-0.704; P < .0001). The 24-month TTNT rate was 87.7% (95% CI, 83.4%-91.0%) with PVR vs 77.2% (95% CI, 71.7%-81.8%) with VR.
MRD analysis demonstrated higher undetectable MRD rates with PVR across all clonoSEQ sensitivity thresholds. Among patients with evaluable end-of-treatment samples (n = 117 per arm), undetectable MRD negativity at a 10–4 sensitivity (MRD4) was achieved in 86.3% of patients who received PVR vs 60.7% of those who received VR (P < .0001); the respective undetectable MRD5 negativity rates were 74.4% vs 50.4% (P = .0002), and the respective undetectable MRD6 negativity rates were 52.1% vs 35.0% (P = .0103).
The PFS benefit with PVR was consistent across prespecified subgroups, including patients with high-risk features, such as unmutated IGHV, del(17p), TP53 mutations, and complex karyotype. Among all patients previously exposed to a covalent BTK inhibitor, the median PFS was NE (95% CI, 41.5-NE) for the PVR arm (n = 256) vs 36.2 months (95% CI, 33.2-not reached [NR]) for the VR arm (n = 254; HR, 0.509; 95% CI, 0.351-0.738; P = .0003).
In the subgroup of patients who had discontinued a prior covalent BTK inhibitor due to progressive disease (n = 181 per arm), the median PFS was 43.3 months (95% CI, 39.2-NE) with PVR vs 33.2 months (95% CI, 28.3-37.5) with VR (HR, 0.444; 95% CI, 0.293-0.673; P < .0001). In patients who had received only 1 prior line of therapy and discontinued a covalent BTK inhibitor due to progressive disease, the median PFS was NR (95% CI, 30.1-NE) for PVR (n = 56) vs 28.3 months (95% CI, 20.5-NE) for VR (n = 54; HR, 0.323; 95% CI, 0.144-0.728; P = .0038).
The overall safety profile of fixed-duration PVR was generally similar to that of VR alone. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.7% of patients in the PVR arm (n = 316) and 98.1% of those in the VR arm (n = 311); grade 3 or higher TEAEs were reported in 78.8% and 73.0% of patients, respectively. The most common any-grade TEAE was neutropenia or decreased neutrophil count (PVR, 60.4%; VR, 54.0%), with grade 3 or higher neutropenia/decreased neutrophil count occurring in 49.7% and 43.7% of patients, respectively.
Discontinuations due to treatment-related TEAEs were low, and these rates were similar between arms (PVR, 5.4%; VR, 5.1%). Deaths due to grade 5 treatment-related TEAEs occurred in 1 patient (0.3%) in the PVR arm and 4 patients (1.3%) in the VR arm.
Treatment with PVR preserved the favorable cardiovascular profile seen with pirtobrutinib and was associated with low rates of any-grade atrial fibrillation or flutter (PVR, 3.5%; VR, 2.6%). Any-grade tumor lysis syndrome occurred in 1.3% of patients in the PVR arm vs 4.2% of those in the VR arm. No new safety signals were identified with the combination.
