FDA Approves Pirtobrutinib for Previously Untreated CLL/SLL

The FDA has approved pirtobrutinib (Jaypirca) for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) harboring no known 17p deletion.¹

This regulatory decision was backed by data from the phase 3 BRUIN CLL-313 trial (NCT05023980). At an estimated median follow-up of 28 months, the median progression-free survival (PFS) was not estimable (NE; 95% CI, NE-NE) in the pirtobrutinib arm (n = 141) vs 33.5 months (95% CI, 32.7-NE) in the bendamustine/rituximab arm (n = 141; HR, 0.20; 95% CI: 0.11-0.37; P < .0001).^1,2

The overall response rate was 94% (95% CI, 89%-98%) in the pirtobrutinib arm vs 81% (95% CI, 73%-87%) in the control arm.² The complete response rates in these respective arms were 13% and 21%.

At the time of the primary PFS analysis, the overall survival (OS) data were not yet mature.¹ The median OS was not reached (NR) in either arm, and 13 deaths had occurred: 3 (2.1%) in the pirtobrutinib arm and 10 (7.1%) in the control arm.

“This approval is grounded in data from BRUIN CLL-313, which showed a significant delay in disease progression for pirtobrutinib compared with chemoimmunotherapy, along with safety and tolerability consistent with its established profile,” Jennifer A. Woyach, MD, a professor, hematologist-oncologist, and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, stated in a news release.³ “Doctors can now consider pirtobrutinib for appropriate patients when initial therapy is needed, not just later in a patient’s treatment journey. Given the efficacy and tolerability of modern targeted therapies, coupled with factors like age or comorbidity, many people diagnosed with CLL or SLL today may only receive 1 or 2 lines of therapy, making initial treatment choices critically important.”

What was the design of BRUIN CLL-313?

This randomized, open-label, active-controlled trial enrolled 282 patients with treatment-naive CLL/SLL without 17p deletion.^1,2 Patients were randomly assigned 1:1 to receive pirtobrutinib at 200 mg once daily until disease progression; or bendamustine at 90 mg/m² on days 1 and 2 of each 28-day cycle in combination with a rituximab product at 375 mg/m² on day 1 of cycle 1 and then at 500 mg/m² on day 1 of subsequent cycles for a maximum of 6 cycles.

Crossover from the control arm to pirtobrutinib monotherapy was allowed upon confirmed disease progression.² In total, 18 patients in the control arm crossed over to receive pirtobrutinib monotherapy.

What additional efficacy findings have been reported from BRUIN CLL-313?

At a median OS follow-up of 32.2 months, the OS data trended in favor of the pirtobrutib arm (HR, 0.257; 95% CI, 0.070-0.934; P = .0261).⁴ The median OS for both arms was NR (95% CI, NE-NE), and the 24-month OS rate was 97.8% (95% CI, 93.3%-99.3%) in the pirtobrutinib arm vs 93.0% (95% CI, 87.0%-96.3%) in the control arm. These findings were consistent with those from a sensitivity analysis that censored 18 patients from the control arm at the time of crossover (HR, 0.249; 95% CI, 0.068-0.906).

What is the safety profile of pirtobrutinib in CLL/SLL?

In BRUIN CLL-313, the most common non-laboratory, any-grade AEs occurring in at least 20% of patients in the pirtobrutinib arm included upper respiratory tract infections (27%), rash (22%), and COVID-19 (21%).^1,2,3,4 The most common grade 3 or 4 laboratory abnormality was decreased neutrophil count. The rate of serious AEs was 28% among patients who received pirtobrutinib.

The prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.^1,2

References

1. FDA approves pirtobrutinib for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. October 2, 2026. Accessed October 2, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pirtobrutinib-previously-untreated-chronic-lymphocytic-leukemia-or-small-lymphocytic
2. Jaypirca. Prescribing information. Lilly; October 2026. Accessed October 2, 2026. https://pi.lilly.com/us/jaypirca-uspi.pdf?s=pi
3. Lilly’s Jaypirca (pirtobrutinib), the first-and-only approved non-covalent BTK inhibitor, receives expanded indication from U.S. FDA for certain patients with previously untreated CLL/SLL. News release. Eli Lilly and Company. October 2, 2026. Accessed October 2, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non-1
4. Jurczak W, Kwiatek M, Czyz J, et al. BRUIN CLL-313: randomized phase III trial of pirtobrutinib versus bendamustine plus rituximab in untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2026;44(6):466-475. doi:10.1200/JCO-25-02380