On December 1, 2023, the FDA accelerated the approval of pirtobrutinib (Jaypirca; Eli Lilly) for the treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received ≥2 lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. The FDA granted this application priority review and orphan drug designations.
Pirtobrutinib was previously approved for the treatment of patients with relapsed or refractory mantle-cell lymphoma after ≥2 lines of systemic therapy, including a BTK inhibitor.
This new approval was based on the results of the phase 1/2 BRUIN study (NCT03740529), an open-label, multicenter, single-arm, clinical trial of pirtobrutinib monotherapy. The study included 108 patients with CLL/SLL who received ≥2 previous lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. The patients received a median of 5 previous lines of therapy (range, 2-11). The most frequent previous lines of BTK inhibitors were ibrutinib (97%), acalabrutinib (9%), and zanubrutinib (0.9%). In all, 77% of the patients had discontinued treatment with the previous BTK inhibitor as a result of progressive or treatment-refractory disease. All patients received pirtobrutinib 200 mg orally once daily until disease progression or unacceptable adverse events.
Overall response rate (ORR) and duration of response (DOR) were the main efficacy measures in the study. All responses in the study were partial responses. The ORR was 72% (95% confidence interval [CI], 63-80); at a median follow-up of 15.7 months, the median DOR was 12.2 months (95% CI, 9.3-14.7).
The most common (≥20%) adverse events with pirtobrutinib, excluding laboratory tests, were fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. The most common (≥10%) grade 3 or 4 laboratory abnormalities with pirtobrutinib were decreased neutrophil and lymphocyte counts and anemia. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and second primary malignancies.
“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 Jaypirca a meaningful advance and much-needed new treatment option for these patients,” said William G. Wierda, MD, PhD, Professor, Medical Director, and CLL section head for the Department of Leukemia, The University of Texas MD Anderson Cancer Center, in a press release.
The recommended dose of pirtobrutinib is 200 mg orally once daily until disease progression or unacceptable adverse events. Dose modifications may be needed with certain adverse events, in patients with severe renal impairment, and in patients receiving strong CYP3A inhibitors or CYP3A inducers.
Continued approval for this indication may be contingent on the verification and description of clinical benefit in a confirmatory trial.