Pirtobrutinib Monotherapy Meets Primary PFS End Point in Treatment-Naive CLL/SLL

Pirtobrutinib (Jaypirca) monotherapy elicited a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with bendamustine plus rituximab (Rituxan; BR) in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without 17p deletions, meeting the primary end point of the phase 3 BRUIN CLL-313 trial (NCT05023980).1

Furthermore, overall survival (OS), a key secondary end point, was trending strongly in favor of pirtobrutinib, although these data were not yet mature at the time of this analysis. Statistical significance for OS will be assessed at the primary OS analysis, which is anticipated to occur in 2026. The overall safety profile of pirtobrutinib in BRUIN CLL-313 was consistent with findings from previously reported trials across various treatment settings.

Together, these data suggest that pirtobrutinib has produced one of the most compelling effect sizes observed with Bruton tyrosine kinase (BTK) inhibitor monotherapy in a frontline CLL trial, according to Eli Lilly and Company, the drug’s developer.

Findings from BRUIN CLL-313 build on the previously reported positive results from the phase 1/2 BRUIN trial (NCT03740529), which provided the basis for the 2023 FDA approval of pirtobrutinib in patients with CLL/SLL who received 2 or more prior lines of therapy; the phase 3 BRUIN CLL-321 trial (NCT04666038), the first randomized, controlled study of pirtobrutinib vs idelalisib (Zydelig) plus rituximab or BR conducted in an exclusively post covalent BTK inhibitor population; and the phase 3 BRUIN CLL-314 trial (NCT05254743) comparing pirtobrutinib with ibrutinib (Imbruvica) in patients with CLL, including those who are treatment naive.1,2

Detailed results from BRUIN CLL-313 will be presented at a medical congress and submitted to a peer-reviewed journal. Such findings, alongside data from BRUIN CLL-314, will form the basis for seeking label expansions in earlier lines of therapy, with global regulatory submissions anticipated later during 2026.

"The results from BRUIN CLL-313 are striking and provocative, across both PFS and OS endpoints, further demonstrating the potential of pirtobrutinib to be a meaningful treatment option for people with untreated CLL/SLL," Jacob Van Naarden, executive vice president and president of Lilly Oncology, stated in a news release.1 "With this third positive phase 3 study, we continue to build the clinical evidence supporting the possible role of pirtobrutinib in a variety of CLL/SLL treatment settings, including treatment-naive, BTK inhibitor–naive and BTK inhibitor–exposed. We look forward to presenting these data, as well as data from the recently announced positive BRUIN CLL-314 study, at upcoming medical meetings and preparing global regulatory submissions, with the goal of making pirtobrutinib an option for a wider group of patients who might benefit."

BRUIN CLL-313 Overview

This open-label, global phase 3 study has enrolled 282 patients with previously untreated CLL/SLL.1,3 Patients were required to have an ECOG performance status of 0 to 2, as well as adequate organ function, creatinine clearance, and platelet levels. Known or suspected Richter's transformation, the presence of 17p deletions, and central nervous system involvement is not permitted. Upon enrollment, patients are randomly assigned 1:1 to receive either oral pirtobrutinib at 200 mg once daily or intravenous BR per labeled doses. Of note, patients in the control arm are permitted to cross over to the pirtobrutinib arm if they experience disease progression.

PFS per blinded independent review committee serves as the study’s primary end point. Secondary end points include investigator and IRC-assessed overall response rate, duration of response, and PFS, OS, time to next treatment, safety and tolerability, and patient-reported outcomes.

The study has a planned completion date of August 2026.

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. News release. Eli Lilly and Company. September 8, 2025. Accessed September 8, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non-0
2. Jaypirca (pirtobrutinib) now approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed September 8, 2025. https://www.prnewswire.com/news-releases/jaypirca-pirtobrutinib-now-approved-by-us-fda-for-the-treatment-of-adult-patients-with-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma-who-have-received-at-least-two-lines-of-therapy-including-a-btk-inhibitor-and--302003695.html#:~:text=INDIANAPOLIS%2C%20Dec.%201%2C%202023,(CLL%2FSLL)%20who%20have
3. A study of pirtobrutinib (LOXO-305) versus bendamustine plus rituximab (BR) in untreated patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN CLL-313). ClinicalTrials.gov. Updated July 23, 2025. Accessed September 8, 2025. https://clinicaltrials.gov/ct2/show/NCT05023980