Eli Lilly announced that its Phase 3 BRUIN CLL‑322 trial of Jaypirca (pirtobrutinib) in combination with venetoclax and rituximab met its primary endpoint, showing a statistically significant and clinically meaningful improvement in progression‑free survival (PFS) compared with venetoclax and rituximab alone in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
The study enrolled 639 patients and randomized them 1:1 to receive pirtobrutinib 200 mg once daily plus venetoclax and rituximab or venetoclax and rituximab alone for up to two years. The addition of pirtobrutinib produced a PFS benefit that was consistent across clinically relevant subgroups, including patients who had previously been treated with covalent BTK inhibitors. While overall survival was trending in favor of the combination, the data were not yet mature.
Safety data were consistent with the known profile of pirtobrutinib, with adverse event rates similar to the control arm. In a related Phase 3 study, median PFS was 11.2 months versus 8.7 months for the control arm (HR 0.58; 95% CI 0.38‑0.89; P = .0105), underscoring the drug’s potency in a setting of prior BTK inhibitor exposure.
Lilly plans to submit the data to regulators later in 2026 to support a label expansion for Jaypirca in CLL/SLL. The trial’s success adds to a growing portfolio of non‑covalent BTK inhibitors that can overcome resistance to covalent agents, addressing an unmet need for patients who progress after first‑line BTK inhibitor therapy. Jaypirca received accelerated approval in 2023 and traditional approval in December 2025 for relapsed or refractory CLL/SLL after a covalent BTK inhibitor.
Jacob Van Naarden, executive vice president and president of Lilly Oncology, said, "BRUIN CLL‑322 was an ambitious trial, building on an effective regimen, and these results outperformed our expectations." He added, "Modern CLL treatment regimens provide such durable disease control that the vast majority of patients see their entire disease course managed by only one or two lines of therapy. For doctors and patients who prefer a time‑limited approach, these BRUIN CLL‑322 data demonstrate that the addition of Jaypirca could further extend the duration of benefit in second line CLL."
The positive topline results reinforce Lilly’s strategy of expanding its oncology pipeline with non‑covalent BTK inhibition and could broaden the therapeutic indications for a drug that has already shown efficacy in earlier Phase 1/2 and Phase 3 studies. The trial represents the fourth positive Phase 3 study for pirtobrutinib, positioning the company to capture a larger share of the CLL/SLL market and to strengthen its competitive stance against other BTK inhibitors and combination regimens.
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