Jaypirca cuts CLL progression risk by 45% in Phase 3 combination trial

Eli Lilly & Co.'s Jaypirca (pirtobrutinib) reduced the risk of disease progression or death by 45% when added to a venetoclax-based regimen in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, meeting the primary endpoint of the Phase 3 BRUIN CLL-322 trial.

"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," Matthew S. Davids, chief of the Division of Lymphoma at Dana-Farber Cancer Institute and lead author on the study, said. "Our study has the potential to establish a new standard of care in this population."

The trial enrolled 639 patients, 79.8% of whom had prior exposure to a covalent BTK inhibitor, and randomized them 1:1 to receive pirtobrutinib plus venetoclax and rituximab (PVR, n=321) or venetoclax and rituximab alone (VR, n=318). At a median follow-up of 27.3 months, the PVR arm showed a hazard ratio of 0.55 (95% CI, 0.40-0.75; p=0.0001) for independent review committee-assessed progression-free survival — meaning a 45% lower risk of progression or death. Median PFS was not reached in the PVR arm (95% CI, 43.3 months-not estimable) versus 39.7 months (95% CI, 35.9-NE) in the VR arm. Among second-line patients whose disease progressed after a first-line covalent BTK inhibitor, the benefit was more pronounced, with a hazard ratio of 0.32 (95% CI, 0.14-0.73) and 24-month PFS rates of 88% versus 52%.

The results mark the first time a Phase 3 study has demonstrated superiority over a venetoclax-containing control arm in CLL, and the data will be presented as a late-breaking oral presentation at the 2026 European Hematology Association Annual Meeting in Stockholm. Overall survival data were not yet mature (HR=0.89; 95% CI, 0.57-1.40), while time to next treatment favored the PVR arm (HR=0.50; 95% CI, 0.35-0.70; nominal p<0.0001). Safety profiles were consistent with each medicine's known tolerability, with Grade 3 or higher adverse events occurring in 78.8% of the PVR arm versus 73.0% in the VR arm. Discontinuation rates due to treatment-related adverse events were similar at 5.4% and 5.1%, respectively. The addition of pirtobrutinib also allowed for downgrading of tumor lysis syndrome risk, with 78% of high-risk patients reclassified to medium or low risk.

The data strengthen Lilly's position in the CLL treatment continuum, where Jaypirca is already approved as a monotherapy for patients previously treated with a covalent BTK inhibitor. Expanding into combination therapy in the second-line setting could significantly broaden the drug's addressable market, given that many CLL patients receive only two lines of therapy. Lilly plans to submit the BRUIN CLL-322 results to global regulatory authorities to expand Jaypirca's label. Investors will watch for the EHA presentation on June 14 for additional subgroup analyses and updated safety data.

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