FDA Grants Traditional Approval to Pirtobrutinib in 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 Bruton tyrosine kinase (BTK) inhibitor.

This regulatory action converts the drug's previous accelerated approval to a full traditional approval. The decision is supported by data from the confirmatory phase 3 BRUIN-CLL-321 trial (NCT04666038), which demonstrated a statistically significant improvement in progression-free survival (PFS) for patients treated with pirtobrutinib compared with investigator’s choice of therapy.

Clinical Trial Data Supporting Approval

BRUIN-CLL-321 was a randomized, open-label, active-controlled study. The trial enrolled 238 patients with CLL or SLL who had received prior treatment with a covalent BTK inhibitor, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa). Notably, patients who had been previously treated with a noncovalent BTK inhibitor were excluded from the study.

Patients were randomized in a 1:1 ratio to receive either pirtobrutinib monotherapy or an investigator’s choice of standard chemoimmunotherapy, consisting of either idelalisib plus rituximab (Rituxan) or bendamustine plus rituximab. The trial permitted patients in the control arm to cross over to receive pirtobrutinib monotherapy upon confirmed disease progression, a design element that ensures ethical treatment but can confound overall survival (OS) analyses.

The primary efficacy outcome was PFS as assessed by an independent review committee utilizing the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.

Efficacy Results

Pirtobrutinib demonstrated a clinically meaningful and statistically significant benefit in PFS. The median PFS in the pirtobrutinib arm was 11.2 months (95% CI, 9.5-11.4), compared with 8.7 months (95% CI, 7.2-10.2) in the investigator’s choice arm. This resulted in a hazard ratio (HR) of 0.58 (95% CI, 0.38-0.89; P=.0105), indicating a 42% reduction in the risk of disease progression or death for patients receiving pirtobrutinib.

An updated analysis of OS, conducted with a median follow-up of 19.8 months, showed an HR of 1.09 (95% CI, 0.68-1.75). Interpretation of this endpoint is limited by the high crossover rate; of the 119 patients randomized to the control arm, 50 (42%) eventually crossed over to receive pirtobrutinib.

Regulatory History and Mechanism

Pirtobrutinib is a highly selective, noncovalent BTK inhibitor. Unlike covalent BTK inhibitors, which bind permanently to the active site of the BTK enzyme, pirtobrutinib binds reversibly. This mechanism allows the drug to maintain activity even in the presence of certain resistance mutations, such as C481, which can prevent covalent inhibitors from binding.

The FDA previously granted pirtobrutinib accelerated approval in 2023 for adults with CLL/SLL who had received at least two prior lines of therapy, specifically including both a BTK inhibitor and a BCL-2 inhibitor. This traditional approval focuses on the broader population of patients previously treated with a covalent BTK inhibitor, solidifying the drug's role in the sequencing of therapy for relapsed disease.

Safety and Administration

The safety profile of pirtobrutinib in the BRUIN-CLL-321 trial was consistent with previous reports. The prescribing information details warnings and precautions for several potential adverse reactions, including infections, hemorrhage, cytopenias, cardiac arrhythmias, and hepatotoxicity. Additionally, there are warnings regarding the potential for secondary primary malignancies and embryo-fetal toxicity.

The recommended dosage for pirtobrutinib is 200 mg taken orally once daily. Treatment should continue until disease progression or the development of unacceptable toxicity.

This review was conducted under the FDA’s Project Orbis and utilized the Assessment Aid, a voluntary submission facilitating the agency's assessment. Pirtobrutinib also holds orphan drug designation for this indication.

REFERENCE

FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. US FDA. Published December 3, 2025. Accessed December 3, 2025. https://tinyurl.com/sxt9t3ps