Fixed-Duration Pirtobrutinib Plus Venetoclax/Rituximab Yields PFS Advantage in R/R CLL/SLL

The addition of pirtobrutinib (Jaypirca) to the fixed-duration regimen of venetoclax (Venclexta) and rituximab (Rituxan) generated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with venetoclax plus rituximab alone in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), meeting the primary end point of the phase 3 BRUIN CLL-322 trial (NCT04965493).¹

The PFS benefit, as assessed by independent central review (ICR), was consistent across subgroups and was observed irrespective of prior exposure to a covalent Bruton tyrosine kinase (BTK) inhibitor. Overall survival (OS) data were mature at the time of this top-line analysis, with a trend favoring the pirtobrutinib arm. Regarding safety, rates of adverse effects and treatment discontinuation were similar between the 2 arms, with the overall safety profile consistent with the individual components of the combination.

Full results from BRUIN CLL-322 will be presented at a future medical conference and shared with global health authorities.

“BRUIN CLL-322 was an ambitious trial, building on an effective regimen, and these results outperformed our expectations,” Jacob Van Naarden, executive vice president and president of Lilly Oncology, stated in a news release. “Modern CLL treatment regimens provide such durable disease control that the vast majority of patients see their entire disease course managed by only 1 or 2 lines of therapy. For doctors and patients who prefer a time-limited approach, these BRUIN CLL-322 data demonstrate that the addition of [pirtobrutinib] could further extend the duration of benefit in second-line CLL. Together with the other phase 3 data recently published from the BRUIN clinical program, these data reinforce the potential role that pirtobrutinib may have, whether as a time-limited combination as a second-line treatment or as a continuously dosed monotherapy in either line of therapy. We look forward to sharing the detailed data later this year and pursuing regulatory approvals to enable broad access.”

In December 2025, the FDA granted traditional approval to pirtobrutinib for the treatment of adult patients with relapsed/refractory CLL/SLL who have previously been treated with a covalent BTK inhibitor, based on data from the phase 3 BRUIN-CLL-321 trial (NCT04666038).² The agent previously received accelerated approval from the FDA in December 2023 for the treatment of adult patients with relapsed/refractory CLL/SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.³

How was the BRUIN CLL-322 trial designed?

BRUIN CLL-322 was a multicenter, open-label, randomized study that enrolled patients at least 18 years of age with CLL/SLL per International Working Group CLL 2018 criteria who had received at least 1 prior line of therapy that could include a covalent BTK inhibitor.⁴ Patients also needed to have adequate organ function, an ECOG performance status of 0 to 2, an estimated creatinine clearance level of at least 30 mL/min, a platelet count of at least 50 x 10⁹/L, a hemoglobin count of at least 8 g/dL, and an absolute neutrophil count of at least 1.0 x 10⁹/L.

Key exclusion criteria comprised known or suspected Richter transformation; prior treatment with a noncovalent BTK inhibitor; prior treatment with venetoclax; and central nervous system involvement.

Investigators randomly assigned 639 patients 1:1 between the 2 study arms to receive pirtobrutinib at 200 mg once per day plus standard-of-care venetoclax plus rituximab, or venetoclax plus rituximab alone.¹ Treatment in both arms continued for up to 2 years, and patients then remained off therapy until disease progression.

Along with the primary end point of PFS per IRC assessment, secondary end points comprised investigator-assessed PFS, OS, time to next treatment, event-free survival, overall response rate, and quality of life.⁴

References

1. Lilly’s Jaypirca (pirtobrutinib) significantly extended progression-free survival when added to a venetoclax time-limited regimen in patients with previously treated CLL/SLL. News release. Eli Lilly and Company. April 13, 2026. Accessed April 13, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-significantly-extended-progression
2. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed April 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
3. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 1, 2023. Accessed April 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
4. A trial of pirtobrutinib (LOXO-305) plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in previously treated chronic lymphocytic leukemia/​small lymphocytic lymphoma (CLL/​SLL) (BRUIN CLL-322). ClinicalTrials.gov. Updated January 29, 2026. Accessed April 13, 2026. https://clinicaltrials.gov/study/NCT04965493