Pirtobrutinib Shows Clinically Meaningful PFS Improvement in Frontline CLL

Pirtobrutinib (Jaypirca; Eli Lilly) demonstrated one of the largest efficacy benefits of a Bruton tyrosine kinase inhibitor (BTKi) on its own in previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a press release from Eli Lilly.1

Results showed that pirtobrutinib significantly extended PFS compared to bendamustine plus rituximab. | Image credit: sovova - stock.adobe.com

The company announced topline data from the BRUIN CLL-313 trial (NCT05023980) showing that pirtobrutinib led to statistically significant and clinically meaningful improvements in progression-free survival (PFS) compared with standard chemoimmunotherapy, meeting the primary end point of the trial.

While longer follow-up is needed to confirm overall survival benefits, the early data support its role as a powerful and versatile option for patients across the treatment spectrum. Lilly plans to submit these results to regulators later this year, with the goal of expanding pirtobrutinib’s label into earlier treatment settings. If approved, pirtobrutinib could become a frontline standard of care for CLL/SLL patients, especially those ineligible for or intolerant of covalent BTK inhibitors.

Pirtobrutinib is the first and only non-covalent (reversible) BTKi approved for clinical use. The drug has already gotten the tentative green light from the FDA with an accelerated approval in relapsed or refractory mantle cell lymphoma and in heavily pretreated patients with CLL/SLL, but until now had not been tested in previously untreated patients.2,3

The phase 3 BRUIN CLL-313 trial enrolled 282 treatment-naïve patients without high-risk 17p deletions. Participants were randomized to receive either pirtobrutinib monotherapy (200 mg orally once daily) or a chemoimmunotherapy regimen of bendamustine plus rituximab (BR).

Results showed that pirtobrutinib significantly extended PFS compared to BR, with an effect size described as “striking and provocative” by company executives. OS data remain immature, but an early trend in favor of pirtobrutinib has been observed, with the final analysis expected in 2026.

BRUIN CLL-313 is the third positive phase 3 trial for pirtobrutinib, with earlier studies focusing on patients previously treated with covalent BTK inhibitors (BRUIN CLL-321) and a head-to-head assessment of pirtobrutinib versus ibrutinib in CLL (BRUIN CLL-314). Collectively, the studies provide a robust foundation for regulatory submissions seeking label expansion into earlier lines of therapy.

“The results from BRUIN CLL-313 are striking across both PFS and OS end points, further demonstrating the potential of pirtobrutinib to be a meaningful treatment option for people with untreated CLL/SLL,” said Jacob Van Naarden, executive vice president and president of Lilly Oncology, in a press release. “With this third positive Phase 3 study, we are building strong clinical evidence to support pirtobrutinib across a variety of treatment settings.”

Other end points from the study include overall response rate, duration of response, time to next treatment, patient-reported outcomes, and safety.

The safety of pirtobrutinib in this trial was consistent with earlier studies. Common side effects associated with the BTKi include cytopenias, such as neutropenia and thrombocytopenia, infections, fatigue, diarrhea, and bruising. Serious side effects include pneumonia and sepsis.

References

1. Lilly's Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, significantly improved progression-free survival in patients with treatment-naïve CLL/SLL. Eli Lilly. Published online September 8, 2025. Accessed September 12, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non-0

2. U.S. FDA approves Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor, for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. Eli Lilly. Published online January 27, 2023. Accessed September 12, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-jaypircatm-pirtobrutinib-first-and-only-non

3. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Published online December 7, 2023. Accessed September 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic