Lilly's Jaypirca on course to reshape post-BTKi CLL treatment after beating venetoclax

Eli Lilly's pirtobrutinib (Jaypirca) became the first therapy to outperform a venetoclax-based regimen in a Phase III study for chronic CLL study. As presented by Lilly via a late-breaking oral presentation at the 2026 European Hematology Association (EHA) Annual Meeting, pirtobrutinib added to a time-limited venetoclax-based regimen in relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL) reduced the risk of progression or death by 45%, potentially establishing a new second-line option for patients previously treated with covalent BTK inhibitors. The presentation represented a full data rundown following the release of topline data in April.

The BRUIN CLL-322 trial enrolled 639 previously treated patients, 79.8% of whom had prior covalent BTK inhibitor exposure — a deliberate design choice that mirrors how CLL is now managed in practice. Patients were randomized to pirtobrutinib plus AbbVie/Genentech's Venclexta (venetoclax) and rituximab (PVR) or venetoclax and rituximab alone (VR). At a median follow-up of 27.3 months, median PFS in the PVR arm was not reached versus 39.7 months in the VR arm (HR=0.55 [95% CI, 0.40–0.75]; p=0.0001). The benefit was consistent across high-risk subgroups including those with TP53 mutation or deletion, unmutated IGHV, and complex karyotype. In an exploratory analysis of second-line patients whose disease progressed after a first-line covalent BTKi, the hazard ratio was 0.32 (95% CI, 0.14–0.73), with 24-month PFS rates of 88% versus 52%.

The safety profile showed limited additive toxicity. Grade ≥3 adverse events occurred in 78.8% of the PVR arm versus 73.0% with VR alone, and treatment discontinuation rates were nearly identical (5.4% versus 5.1%). Notably, pirtobrutinib's three-cycle lead-in before venetoclax introduction downgraded tumor lysis syndrome risk in a substantial proportion of patients — 78% of those classified as high-risk were moved to medium or low risk — a clinically meaningful finding given the complexity of venetoclax ramp-up. Overall survival data remain immature.

Competitive context

Pirtobrutinib is a non-covalent, reversible BTK inhibitor, mechanistically distinct from covalent agents such as BeiGene's Brukinsa (zanubrutinib) and AstraZeneca/Acerta's Calquence (acalabrutinib). Its key differentiator is retained activity against the BTK C481S resistance mutation that commonly drives progression on covalent BTKi therapy. The drug already holds US FDA approval as monotherapy for CLL/SLL patients who have received a prior covalent BTKi. BRUIN CLL-322 now positions it as a potential combination partner in the second-line setting, a meaningfully different commercial and clinical proposition. Cross-trial comparisons are limited, but the venetoclax plus rituximab control arm in BRUIN CLL-322 — with a median PFS approaching 40 months — performed comparably to historical benchmarks from the MURANO trial, lending credibility to the trial's internal comparison.

The result also has implications for treatment architecture in CLL more broadly. As Lilly noted in its presentation, many patients in the modern era receive only two lines of therapy, making the depth and durability of second-line treatment increasingly consequential. A regimen that combines the resistance-overcoming mechanism of pirtobrutinib with the time-limited, treatment-free interval of venetoclax-based therapy addresses both the efficacy and quality-of-life dimensions that now shape prescribing decisions. Lilly plans to submit BRUIN CLL-322 data to global regulatory authorities to expand Jaypirca's label, with the data presented as a late-breaking oral at the 2026 European Hematology Association Annual Meeting.

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