FDA Approves Pirtobrutinib for Relapsed or Refractory CLL/SLL

The FDA has granted traditional approval to pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have previously been treated with a covalent BTK inhibitor.1

This regulatory decision was supported by findings from the phase 3 BRUIN CLL-321 trial (NCT04666038), in which pirtobrutinib produced a median progression-free survival (PFS) of 11.2 months (95% CI, 9.5-11.4) vs 8.7 months (95% CI, 7.2-10.2) with investigator’s choice of either idelalisib (Zydelig) plus rituximab (Rituxan; IR) or bendamustine (Avastin) plus rituximab (BR; HR, 0.58; 95% CI, 0.38, 0.89; P = .0105).

Of note, 50 of the 119 patients in the investigator's choice arm crossed over to the pirtobrutinib arm.

Updated results from this trial, which were previously presented at the 2024 ASH Annual Meeting, showed that, at a median follow-up of 19.8 months, the HR for overall survival (OS) was 1.09 (95% CI, 0.68-1.75).2 The 18-month OS rates in the pirtobrutinib vs investigator's choice arms were 73.4% (95% CI, 63.9%-80.7%) at a median follow-up of 20.4 months compared with 70.8% (95% CI, 60.9%-78.7%) at a median follow-up of 19.3 months, respectively. However, investigators noted that the analysis was confounded because 76% of patients were allowed to cross over following progression.

Notably, the FDA previously granted accelerated approval to pirtobrutinib in 2023 for the treatment of adults with CLL/SLL who received 2 or more prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.1

What was the design of BRUIN-CLL-321?

This randomized, open-label, active-controlled trial enrolled 238 patients with previously-treated, BTK inhibitor-exposed, confirmed CLL/SLL per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL).1,2 Patients were not eligible for the study if they were previously treated with a non-covalent BTK inhibitor. There was no limit on prior lines of therapy, and a prior history of atrial fibrillation was allowed.

Patients were stratified by the presence of 17p deletions (yes vs no) and prior venetoclax (Venclexta) exposure (yes vs no).

Upon enrollment, patients were randomly assigned 1:1 to receive either pirtobrutinib monotherapy (n = 119) or investigator’s choice of IR or BR (n = 119). Crossover to the experimental arm was permitted following disease progression.

The study's primary end point was PFS per independent review committee assessment. Other key end points included PFS per investigator assessment, OS, event-free survival (EFS), time to next treatment (TTNT), and safety.

What additional efficacy data have been reported from BRUIN-CLL-321?

In addition to its demonstrated PFS benefit, pirtobrutinib was shown to reduce the risk of an event by 61% (HR, 0.39; 95% CI, 0.28-0.53; P < .0001).2 The monotherapy produced a median EFS of 14.1 months (95% CI, 11.4-17.0) at a median follow-up of 19.4 months vs 7.6 months (95% CI, 4.8-8.8) with investigator's choice of therapy at a median follow-up of 18.7 months.

Moreover, treatment with pirtobrutinib reduced the risk of starting next treatment or death by 63%, with a median TTNT of about 24 months (HR, 0.37; 95% CI, 0.25-0.52; P < .0001). Patients in the pirtobrutinib arm achieved a median TTNT of 24.0 months (95% CI, 17.8-29.7) at a median follow-up of 20.0 months vs 10.9 months (95% CI, 8.7-12.5) in the investigator's choice arm at a median follow-up of 20.2 months.

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

Regarding safety, the most common adverse effects (AEs) observed in at least 20% of patients treated with pirtobrutinib included fatigue, musculoskeletal pain, diarrhea, COVID-19, bruising, and cough. Common grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients include decreased neutrophil count, decreased platelet count, decreased hemoglobin levels, and decreased lymphocyte count.3

Safety data from BRUIN-CLL-321 reinforce pirtobrutinib's tolerability, showing low rates of discontinuation due to treatment-related AEs with the monotherapy (5.2%) vs IR/BR (21.1%).2 Moreover, after adjusting for exposure, the incidence of any-grade treatment-emergent AEs was lower with pirtobrutinib than IR/BR.

The agent's recommended dose is 200 mg orally once daily until disease progression or unacceptable toxicity.1

References

1. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed December 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic?utm_medium=email&utm_source=govdelivery
2. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886-886. doi: 10.1182/blood-2024-198147
3. Pirtobrutinib. Prescribing information. FDA; 2024. Accessed December 3, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216059s002lbl.pdf