Lilly presented Phase III data for Jaypirca (pirtobrutinib) at the European Hematology Association (EHA) 2026 annual meeting in Stockholm, demonstrating for the first time that a three-drug combination can outperform a venetoclax-containing control regimen in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
Key Takeaways
- Adding Jaypirca to a venetoclax‑containing regimen reduced progression or death risk by 45% (HR 0.55)—the first Phase III trial to demonstrate superiority over a venetoclax‑based control in any CLL setting.
- Lilly plans global submissions to expand Jaypirca’s label into combination therapy for relapsed/refractory CLL/SLL previously treated with a covalent BTK inhibitor.
- While Jaypirca is currently the only approved non‑covalent BTK inhibitor, next‑generation BTK degraders from Roche/Nurix, BeOne Medicines, and Newave are advancing toward Phase III trials targeting the same patient population.
While the data are promising and gives Lilly an edge in CLL/SLL, the window for the US drugmaker to capitalize could be small as it competes in a highly contested BTK inhibitor market with the added pressure of head-to head trials from Roche, BeOne Medicines on the horizon.
In the Phase III BRUIN CLL-322 trial, adding Jaypirca—a non-covalent BTK inhibitor—to AbbVie and Roche’s Venclexta (venetoclax) plus rituximab reduced the risk of disease progression or death by 45% compared with venetoclax plus rituximab (VR) alone (HR=0.55; p=0.0001). Thereby, meeting the trial’s primary endpoint of independent review committee (IRC)-assessed PFS.
Lilly plans to submit the data to global regulators in the coming months to expand Jaypirca’s label by adding a time-limited combination regimen for patients with prior exposure to covalent BTK inhibitors.
Phase III Data: Consistency Across High-Risk Subgroups
The BRUIN CLL-322 trial enrolled 639 patients with relapsed or refractory CLL/SLL, 79.8% of whom had prior exposure to a covalent BTK inhibitor. At a median follow‑up of 27.3 months, progression‑free survival (PFS) by independent review favored the triplet (Jaypirca + venetoclax + rituximab, or PVR) over VR alone, with median PFS not yet reached in the PVR arm versus 39.7 months for VR (HR 0.55).
The benefit remained consistent across pre-specified subgroups. Among prior covalent BTK inhibitor-exposed patients, PVR yielded a median PFS not reached, compared with 36.2 months with VR.
In an exploratory analysis of second-line patients treated post-covalent BTK inhibitor, the advantage was even more pronounced, as median PFS in the PVR arm was not reached versus 28.3 months for VR (HR 0.32) and 24-month PFS rates of 88% versus 52%. High-risk features including unmutated IGHV, TP53 mutation and/or 17p deletion, and
