Pirtobrutinib Wins Traditional FDA Approval in CLL and SLL

The FDA has approved pirtobrutinib (Jaypirca) treatment for adults with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received prior treatment with a covalent BTK inhibitor, according to a release from the regulatory agency.

The efficacy of pirtobrutinib was evaluated in the phase 3 BRUIN-CLL-321 (NCT04666038) study. This randomized, open-label, active-controlled trial enrolled 238 patients with previously treated CLL/SLL, all of whom had prior exposure to a covalent BTK inhibitor. Participants were randomly assigned 1:1 to receive either pirtobrutinib or the investigator’s choice of idelalisib (Zydelig) plus rituximab (Rituxan; IR) or bendamustine (Treanda) plus rituximab (BR). Notably, patients assigned to the investigator’s choice arm were allowed to cross over to pirtobrutinib monotherapy following confirmed disease progression.

Moreover, the primary end point was progression-free survival (PFS) as evaluated by an independent review committee according to 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.

The median PFS for patients receiving pirtobrutinib was 11.2 months (95% CI: 9.5, 11.4) compared with 8.7 months (95% CI, 7.2-10.2) in the IR/BR arm (HR, of 0.58; 95% CI, 0.38-0.89; P = .0105). Among the 119 patients in the investigator’s choice arm, 50 crossed over to pirtobrutinib therapy. Additionally, the release from the regulatory agency noted 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).

The prescribing information, according to the regulatory update, includes warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrhythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.

The recommended dose of pirtobrutinib is 200 mg orally once daily, continued until disease progression or unacceptable toxicity occurs.

Eligibility Criteria and Enrollment Overview for BRUIN-CLL-321

Eligible patients for BRUIN-CLL-321 included adults 18 years or older with a confirmed diagnosis of CLL or SLL requiring treatment per 2018 iwCLL criteria and prior exposure to a covalent BTK inhibitor. Patients were required to have an ECOG performance status of 0, 1, or 2, adequate hematologic function, and sufficient organ function.

Exclusion criteria included known or suspected Richter transformation or central nervous system (CNS) involvement, active uncontrolled infections or autoimmune cytopenias, recent allogeneic transplant or CAR-T therapy within 60 days, active hepatitis B/C or CMV infection, significant cardiovascular disease, prior exposure to non-covalent BTK inhibitors, need for therapeutic warfarin or CYP3A4 modulators, recent live vaccination, or known hypersensitivity to study drugs or rituximab.

BRUIN-CLL-321 Phase 3 Trial Demonstrates Efficacy vs Standard Regimens

The release from the FDA also went on to explain that, in 2023, the FDA granted accelerated approval for pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor, for adult patients with CLL/SLL who have undergone at least two prior therapies, including a BTK inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.

The distinct mechanism of action of pirtobrutinib enables efficacy in patients who have already been treated with a prior BTK inhibitor.

“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of [pirtobrutinib] a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, explained in a news release from Eli Lilly, the manufacturer of pirtobrutinib. “[Pirtobrutinib] offers a new treatment option and different approach to targeting BTK, providing clinical benefit for a high proportion of patients with CLL or SLL in the BRUIN Phase 1/2 trial whose disease progressed following treatment with a covalent BTK inhibitor and with a BCL-2 inhibitor.”

Wierda is professor, medical director, and CLL section head for the Department of Leukemia at The University of Texas MD Anderson Cancer Center, in Houston.

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. Study of LOXO-305 (Pirtobrutinib) Versus Investigator's Choice (Idelalisib Plus Rituximab or Bendamustine Plus Rituximab) in Patients With Previously Treated Chronic Lymphocytic Leukemia (CLL)/​Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-321). ClinicalTrials.gov. Updated April 20, 2025. Accessed December 3, 2025. https://clinicaltrials.gov/study/NCT04666038
3. FDA Grants Pirtobrutinib Accelerated Approval to Treat CLL/SLL in the Third Line. Oncology Nursing News. December 3, 2023. https://www.oncnursingnews.com/view/fda-grants-pirtobrutinib-accelerated-approval-to-treat-cll-sll-in-the-third-line