By VETTAPHARMA reporter – Derek Roche: Eli Lilly announced that Jaypirca (pirtobrutinib) significantly improved progression-free survival (PFS) when added to a fixed-duration regimen of venetoclax and rituximab in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
In the pivotal Phase 3 BRUIN CLL-322 study, the combination reduced the risk of disease progression or death by 45% compared with venetoclax plus rituximab alone, marking the first Phase 3 trial to demonstrate superiority over a venetoclax-containing control regimen in CLL.
The global, randomized Phase 3 trial enrolled 639 patients with relapsed or refractory CLL/SLL, of whom 79.8% had previously received a covalent Bruton tyrosine kinase (BTK) inhibitor, reflecting current treatment patterns. Patients were randomized to receive either Jaypirca 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 primary endpoint of independent review committee-assessed PFS was met with a hazard ratio of 0.55 (95% CI, 0.40–0.75; p=0.0001). Median PFS was not reached in the Jaypirca arm compared with 39.7 months in the control arm.
The PFS benefit was consistent across predefined patient subgroups, including those previously treated with covalent BTK inhibitors, patients who discontinued prior BTK inhibitor therapy because of disease progression, and individuals with high-risk disease features such as TP53 mutation, 17p deletion, unmutated IGHV, or complex karyotype. In an exploratory analysis of second-line patients progressing after first-line covalent BTK inhibitor therapy, the hazard ratio for disease progression or death was 0.32, with 24-month PFS rates of 88% for the Jaypirca combination versus 52% for the control regimen.
Overall survival data were immature at the time of analysis (HR 0.89), while the secondary endpoint of time to next treatment also favored the Jaypirca combination (HR 0.50; nominal p<0.0001). The safety profile was consistent with the known profiles of the individual therapies, with similar rates of Grade ≥3 adverse events between treatment arms (78.8% vs. 73.0%) and comparable treatment discontinuation rates due to treatment-related adverse events (5.4% vs. 5.1%).
Lilly stated that it plans to submit the BRUIN CLL-322 results to global regulatory authorities to support expansion of Jaypirca’s approved indications. The data will be presented as a late-breaking oral presentation at the 2026 European Hematology Association (EHA) Annual Meeting.
Quick FAQs
1. What Is Jaypirca?
Jaypirca (pirtobrutinib) is a highly selective, non-covalent Bruton tyrosine kinase (BTK) inhibitor approved for certain patients with relapsed or refractory CLL/SLL and mantle cell lymphoma.
2. What Happened?
Lilly reported positive Phase 3 BRUIN CLL-322 results showing that adding Jaypirca to venetoclax and rituximab significantly improved progression-free survival in previously treated CLL/SLL.
3. What Is The BRUIN CLL-322 Study?
BRUIN CLL-322 is a global, randomized, open-label Phase 3 trial comparing time-limited Jaypirca plus venetoclax and rituximab with venetoclax and rituximab alone in 639 patients with relapsed or refractory CLL/SLL.
4. What Is CLL/SLL?
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are closely related B-cell malignancies that often require multiple lines of therapy as the disease relapses or becomes resistant to treatment.
5. What Were The Key Results?
The Jaypirca combination reduced the risk of disease progression or death by 45%, prolonged progression-free survival, and demonstrated consistent benefit across multiple high-risk patient subgroups while maintaining a manageable safety profile.
6. Why Is This Important?
The study is the first Phase 3 trial to demonstrate superiority over a venetoclax-containing control regimen in CLL and may establish a new time-limited treatment option for patients with previously treated disease, particularly those previously exposed to covalent BTK inhibitors.
