Eli Lilly and Company has announced results from the phase 3 BRUIN CLL-322 clinical trial of Jaypirca (pirtobrutinib), a non-covalent Bruton Tyrosine Kinase (BTK) inhibitor, plus venetoclax and rituximab versus venetoclax and rituximab in patients with relapsed or refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL). The study met its primary endpoint of Independent Review Committee (IRC)-assessed Progression-Free Survival (PFS), demonstrating that the addition of pirtobrutinib to a 2-year venetoclax plus rituximab regimen reduced the risk of disease progression or death by 45 percent (HR=0.55 [95 percent CI, 0.40-0.75]; p=0.0001).

These data will be highlighted in a late-breaking oral presentation at the 2026 European Hematology Association (EHA) Annual Meeting taking place in Stockholm, Sweden, as well as featured in the meeting's press program.

Matthew S. David, MD, MMSc, Chief of the Division of Lymphoma, Dana-Farber Cancer Institute, who is the lead author on the study, said, "These results from BRUIN CLL-322 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. Time-limited regimens are an important option in CLL care and provide patients with meaningful treatment-free intervals. In the context of the modern CLL treatment landscape, where many patients may only receive 2 lines of therapy, these results speak to the potential benefits that improving second-line therapy can have. Our study has the potential to establish a new standard of care in this population."

BRUIN CLL-322 enrolled 639 relapsed or refractory patients, with 79.8 percent having prior covalent BTK inhibitor exposure, who were randomised 1:1 to receive pirtobrutinib plus venetoclax and rituximab (PVR, n=321) or venetoclax and rituximab alone (VR, n=318).

Patients in the PVR arm received 3 cycles of pirtobrutinib and the first 3 cycles of rituximab before venetoclax was introduced. The efficacy results are based on a February 2, 2026 data cutoff.

At a median follow-up of 27.3 months, the primary endpoint of IRC-assessed PFS was significantly improved with the addition of pirtobrutinib to VR compared to VR alone (HR=0.55 [95 percent CI, 0.40-0.75]; p=0.0001).

Median PFS in the PVR arm was not reached (95 percent CI, 43.3-NE), versus 39.7 months (95 percent CI, 35.9-NE) in the VR arm. The PFS results were consistent across prespecified subgroups, including patients with prior covalent BTK inhibitor exposure (PVR: not reached [95 percent CI, 41.5-NE] versus VR: 36.2 months [95 percent CI, 33.2-NE]), those who discontinued prior covalent BTK inhibitor due to progressive disease (PVR: 43.3 months [95 percent CI, 39.2-NE] versus VR: 33.2 months [95 percent CI, 28.3-37.5]), as well as those with high-risk features such as unmutated IGHV, TP53 mutation and/or 17p deletion, and/or complex karyotype.

In an exploratory analysis of second-line patients whose disease progressed after a first-line covalent BTK inhibitor, the median PFS was not reached (95 percent CI, 30.1-NE) in the PVR arm and was 28.3 months (95 percent CI, 20.5-NE) in the VR arm (HR=0.32 [95 percent CI, 0.14-0.73]), with 24-month PFS rates of 88 percent (95 percent CI, 75.7-94.6) and 52 percent (95 percent CI, 34.7-66.2), respectively, and consistent benefit was observed regardless of the specific prior covalent BTK inhibitor received.

Overall Survival (OS), a key secondary endpoint, was not yet mature at this analysis (HR=0.89 [95 percent CI, 0.57-1.40]), and final testing of OS superiority is planned at a future date. An additional secondary endpoint, Time to Next Treatment (TTNT), consistently favored the pirtobrutinib combination regimen (HR=0.50 [95 percent CI, 0.35-0.70]; nominal p<0.0001).

The overall safety profile of this regimen in BRUIN CLL-322 was consistent with the known safety profile of each medicine, with little additive toxicity observed with the addition of pirtobrutinib to venetoclax and rituximab. Rates of Grade ≥3 Adverse Events (AEs) were similar with PVR compared to VR (78.8 percent versus 73.0 percent, respectively). Low rates of any grade atrial fibrillation/flutter (3.5 percent versus 2.6 percent, respectively), hypertension (12.0 percent versus 7.4 percent, respectively), and hemorrhage (14.2 percent versus 10.6 percent, respectively) were seen with PVR versus VR. Grade ≥3 clinical AEs of interest included neutropenia (50.3 percent versus 43.7 percent, respectively) and tumor lysis syndrome (0.9 percent versus 3.9 percent, respectively) in the PVR and VR arms.

Discontinuation rates due to treatment-related AEs were similar across the PVR and VR study arms (5.4 percent versus 5.1 percent, respectively). The addition of pirtobrutinib to VR also allowed for downgrading of tumor lysis risk, with 78 percent of high-risk patients downgraded to medium (n=20) or low risk (n=18), and 61 percent of medium-risk patients downgraded to low risk.

Jacob Van Naarden, Executive Vice President (EVP) and President, Lilly Oncology, said, "These remarkable findings support the potential addition of 2 years of Jaypirca to a time-limited venetoclax-based regimen in relapsed or refractory CLL. BRUIN CLL-322 enrolled mostly covalent BTK inhibitor-pretreated population, ensuring that these results have applicability to the modern CLL treatment landscape where covalent BTK inhibitor use is now common. Additionally, these data further strengthen the unique body of evidence for Jaypirca across the CLL continuum, from monotherapy to combination therapy and across multiple settings where CLL patients need effective treatment."`

Lilly plans to submit results from the BRUIN CLL-322 study to global regulatory authorities with the goal of further expanding Jaypirca's label.