Eli Lilly 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 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 two-year venetoclax plus rituximab regimen reduced the risk of disease progression or death by 45% (HR=0.55 [95% 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 programme.
The study enrolled 639 relapsed or refractory patients, with 79.8% having prior covalent BTK inhibitor exposure, who were randomized 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 three cycles of pirtobrutinib and the first three cycles of rituximab before venetoclax was introduced. The efficacy results are based on a February 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% CI, 0.40-0.75]; p=0.0001). Median PFS in the PVR arm was not reached (95% CI, 43.3-NE), versus 39.7 months (95% 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% CI, 41.5-NE] versus VR: 36.2 months [95% CI, 33.2-NE]), those who discontinued prior covalent BTK inhibitor due to progressive disease (PVR: 43.3 months [95% CI, 39.2-NE] versus VR: 33.2 months [95% 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% CI, 30.1-NE) in the PVR arm and was 28.3 months (95% CI, 20.5-NE) in the VR arm (HR=0.32 [95% CI, 0.14-0.73]), with 24-month PFS rates of 88% (95% CI, 75.7-94.6) and 52% (95% 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% 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 favoured the pirtobrutinib combination regimen (HR=0.50 [95% CI, 0.35-0.70]; nominal p<0.0001).
The overall safety profile of this regimen in 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% versus 73.0%, respectively). Low rates of any grade atrial fibrillation/flutter (3.5% versus 2.6%, respectively), hypertension (12.0% versus 7.4%, respectively), and haemorrhage (14.2% versus 10.6%, respectively) were seen with PVR versus VR.
Grade ≥3 clinical AEs of interest included neutropenia (50.3% versus 43.7%, respectively) and tumour lysis syndrome (0.9% versus 3.9%, 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% versus 5.1%, respectively). The addition of pirtobrutinib to VR also allowed for downgrading of tumour lysis risk, with 78% of high-risk patients downgraded to medium (n=20) or low risk (n=18), and 61% of medium-risk patients downgraded to low risk.
Lilly plans to submit results from the CLL-322 study to global regulatory authorities with the goal of further expanding.
