Eli Lilly and Company reported that adding Jaypirca (pirtobrutinib) to a time-limited venetoclax and rituximab regimen significantly reduced the risk of disease progression or death in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). In a Phase 3 study comparing Jaypirca plus venetoclax and rituximab to venetoclax and rituximab alone, the combination met its primary endpoint of independent review committee–assessed progression-free survival, cutting the risk of progression or death by 45% (hazard ratio 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 Annual Meeting in Stockholm and featured in the meeting’s press program.
The trial enrolled 639 patients with relapsed or refractory disease, 79.8% of whom had received a prior covalent BTK inhibitor, reflecting current treatment patterns. Patients were randomized 1:1 to receive Jaypirca plus venetoclax and rituximab (PVR, n=321) or venetoclax and rituximab alone (VR, n=318). After a median follow-up of 27.3 months, median progression-free survival was not reached in the PVR arm (95% CI, 43.3–not estimable) versus 39.7 months (95% CI, 35.9–not estimable) in the VR arm. The benefit was consistent across prespecified subgroups, including patients with prior covalent BTK inhibitor exposure, those who discontinued a covalent BTK inhibitor due to progression, and those with high-risk features such as unmutated IGHV, TP53 mutation and/or 17p deletion, and complex karyotype.
In an exploratory analysis of second-line patients whose disease had progressed after first-line covalent BTK inhibitor therapy, median progression-free survival was not reached in the PVR arm (95% CI, 30.1–not estimable) versus 28.3 months (95% CI, 20.5–not estimable) in the VR arm (hazard ratio 0.32; 95% CI, 0.14–0.73). At 24 months, progression-free survival rates in this subgroup were 88% (95% CI, 75.7–94.6) with PVR and 52% (95% CI, 34.7–66.2) with VR, with consistent benefit regardless of which covalent BTK inhibitor patients had previously received. Time to next treatment also favored the Jaypirca-containing regimen (hazard ratio 0.50; 95% CI, 0.35–0.70; nominal p<0.0001). Overall survival, a key secondary endpoint, was not yet mature at this analysis (hazard ratio 0.89; 95% CI, 0.57–1.40), and final testing of overall survival superiority is planned at a later date.
Investigators said the findings provide the first robust evidence that adding a non-covalent BTK inhibitor to a time-limited venetoclax-based regimen can further extend remission in previously treated CLL, including patients previously exposed to BTK inhibitors. They emphasized the importance of time-limited strategies in CLL to offer meaningful treatment-free intervals, particularly in a landscape where many patients may receive only two lines of therapy. Lilly noted that the results support the potential for Jaypirca plus venetoclax and rituximab to become a new standard of care in this population and further strengthen the evidence base for Jaypirca across the CLL continuum.
The safety profile of the combination was consistent with the known profiles of Jaypirca, venetoclax and rituximab, with little additive toxicity. Rates of grade 3 or higher adverse events were similar between the PVR and VR arms (78.8% vs 73.0%, respectively). Any-grade atrial fibrillation or flutter occurred in 3.5% vs 2.6%, hypertension in 12.0% vs 7.4%, and hemorrhage in 14.2% vs 10.6% in the PVR and VR groups, respectively. Grade 3 or higher neutropenia was reported in 50.3% vs 43.7%, and tumor lysis syndrome in 0.9% vs 3.9%. Discontinuation rates due to treatment-related adverse events were comparable (5.4% vs 5.1%). The addition of Jaypirca also allowed downgrading of tumor lysis syndrome risk, with 78% of high-risk patients and 61% of medium-risk patients reclassified to lower risk categories.
Lilly plans to submit the new data to global regulators with the goal of expanding the Jaypirca label. The company is continuing to study Jaypirca in CLL/SLL across multiple Phase 3 trials, evaluating its role from monotherapy to combination regimens and in various treatment settings.
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