On December 3, the U.S. Food and Drug Administration (FDA) granted traditional approval to pirtobrutinib (Jaypirca), a noncovalent Bruton’s tyrosine kinase (BTK) inhibitor, for adults with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. In 2023, the FDA granted accelerated approval to pirtobrutinib for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
BRUIN-CLL-321
Efficacy was evaluated in BRUIN-CLL-321 (ClinicalTrials.gov identifier NCT04666038), a randomized, open-label, active-controlled trial that included 238 patients who were previously treated for CLL/SLL, including with a covalent BTK inhibitor; patients previously treated with a noncovalent BTK inhibitor were not permitted. Patients were randomly assigned 1:1 to receive either pirtobrutinib or investigator’s choice of idelalisib plus a rituximab product (IR) or bendamustine plus a rituximab product (BR). Crossover to pirtobrutinib monotherapy was permitted for patients in the investigator’s choice arm after confirmed disease progression.
The primary efficacy outcome measure was progression-free survival as assessed by an independent review committee using 2018 International Workshop on CLL criteria. Median progression-free survival was 11.2 months (95% confidence interval [CI] = 9.5–11.4 months) in the pirtobrutinib arm and 8.7 months (95% CI = 7.2–10.2 months) in the investigator’s choice of IR/BR arm (hazard ratio [HR] = 0.58, 95% CI = 0.38–0.89, P = .0105). Of the 119 patients in the investigator’s choice arm, 50 crossed over to receive ibrutinib. At an updated analysis with a median follow-up time of 19.8 months, the HR for overall survival was 1.09 (95% CI = 0.68–1.75).
The prescribing information for pirtobrutinib includes warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.
The recommended pirtobrutinib dose is 200 mg orally once daily until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. Pirtobrutinib received Orphan Drug designation.
