Jaypirca Regimen Cuts Progression Risk by 45% in Relapsed CLL

Eli Lilly’s non‑covalent BTK inhibitor Jaypirca® (pirtobrutinib) reduced the risk of progression or death by 45% in the Phase 3 BRUIN CLL‑322 trial (NCT04965493) when added to venetoclax and rituximab, marking the first venetoclax‑based regimen to be surpassed in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). The findings could establish a new treatment option for previously treated patients, particularly those with prior BTK inhibitor exposure.

Study Design and Results

BRUIN CLL‑322 enrolled 639 patients globally, with nearly 80% previously treated with a covalent BTK inhibitor. Participants were randomized to receive either 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, median progression‑free survival (PFS) was not reached in the PVR arm compared with 39.7 months in the VR arm (HR=0.55; 95% CI, 0.40–0.75; p=0.0001). Benefit was consistent across high‑risk subgroups, including TP53 mutations, 17p deletion, unmutated IGHV, complex karyotype, and prior BTK inhibitor exposure.

Subgroup Benefit

In patients progressing after first‑line covalent BTK inhibitor therapy, median PFS was not reached with PVR versus 28.3 months with VR (HR=0.32), with 24‑month PFS rates of 88% versus 52%. Time to next treatment also favored the triple regimen (HR=0.50; nominal p<0.0001). Overall survival data remain immature and will be evaluated in future analyses.

Clinical Context

Pirtobrutinib is a highly selective, non‑covalent Bruton tyrosine kinase (BTK) inhibitor that maintains activity in patients previously treated with covalent BTK inhibitors. Combined with venetoclax and rituximab, the regimen offers a time‑limited treatment approach that may extend remission duration in relapsed disease. According to lead investigator Matthew Davids, MD, of Dana‑Farber Cancer Institute, the findings provide the first robust evidence supporting a time‑limited BTK inhibitor‑based regimen in patients previously exposed to BTK‑directed therapy and may help redefine second‑line treatment strategies.

Safety Profile

The safety profile was consistent with the known profiles of the individual medicines. Grade ≥3 adverse events occurred in 78.8% of patients receiving PVR and 73.0% receiving VR. Neutropenia was more frequent with PVR (50.3% vs 43.7%), while tumor lysis syndrome occurred less often (0.9% vs 3.9%), enabling downgrading of TLS risk before venetoclax initiation in many patients. Rates of atrial fibrillation, hypertension, and hemorrhage remained low. Treatment discontinuations due to adverse events were similar between groups at approximately 5%.

Clinical Path Forward

Lilly plans global regulatory submissions to expand pirtobrutinib’s label in CLL/SLL, positioning it as the first BTK inhibitor to demonstrate superiority in a time‑limited regimen post‑BTK exposure. Additional Phase 3 studies are ongoing across earlier lines of therapy and broader patient populations, further strengthening the evidence base for pirtobrutinib in CLL.

Reference

Lilly’s Jaypirca (pirtobrutinib) significantly reduced the risk of disease progression or death by 45% when added to a venetoclax time-limited regimen in people with previously treated CLL/SLL | Eli Lilly and Company