Chronic lymphocytic leukemia cells: © Mari-stocker – stock.adobe.com
Positive topline results from the phase 3 BRUIN CLL-314 study (NCT05254743) demonstrated that pirtobrutinib (Jaypirca), a novel noncovalent BTK inhibitor, met its primary end point of noninferiority in overall response rate (ORR) compared with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This trial is notable as the first head-to-head study comparing a BTK inhibitor against ibrutinib in CLL that included treatment-naive patients.1
The randomized, open-label BRUIN CLL-314 study enrolled 650 patients with CLL/SLL, encompassing both treatment-naive and previously treated but BTK inhibitor-naive patients. Patients received either pirtobrutinib 200 mg orally once daily or ibrutinib 420 mg orally once daily.
While the primary end point of ORR, as assessed by a blinded independent review committee (IRC), favored pirtobrutinib, detailed ORR percentages will be announced at a medical conference later this year. Importantly, progression-free survival (PFS) data, though still immature, trended in favor of pirtobrutinib, with a formal PFS analysis anticipated in future reporting. No detriment was observed for overall survival (OS). The safety profile of pirtobrutinib in this trial was consistent with previously reported studies, reinforcing its known tolerability.
This positive outcome marks the second successful phase 3 study for pirtobrutinib, building upon the foundation laid by the earlier BRUIN phase 1/2 trial and the phase 3 BRUIN CLL-321 trial (NCT04664421). The BRUIN CLL-321 trial previously supported the accelerated approval of pirtobrutinib for adult patients with CLL/SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.2 Its approval for relapsed or refractory mantle cell lymphoma (MCL) after at least 2 lines of systemic therapy, including a BTK inhibitor, was also based on response rate data.
Another ongoing phase 3 study, BRUIN CLL-313 (NCT05221372), is expected to yield results later in 2025. The combined data from BRUIN CLL-313 and BRUIN CLL-314 are intended to support global regulatory submissions for pirtobrutinib in broader CLL/SLL indications.1
Pirtobrutinib is distinguished as a highly selective, noncovalent inhibitor of the BTK enzyme. Its mechanism of action allows it to bind to BTK in a different manner than covalent inhibitors like ibrutinib, potentially overcoming resistance mechanisms that emerge with irreversible BTK inhibitors. This reversible binding characteristic may contribute to its efficacy in patients who have previously been treated with, or become resistant to, other BTK inhibitors. The drug is currently available as 100 mg or 50 mg oral tablets, typically prescribed as a once-daily 200 mg dose.
From a safety perspective, clinicians should be aware of the established adverse reactions associated with pirtobrutinib. Fatal and serious infections (including bacterial, viral, fungal, and opportunistic) have occurred, with grade ≥3 infections reported in 24% of hematologic malignancy patients (14% pneumonia) and 32% in patients with CLL/SLL (8% fatal). Prophylaxis and close monitoring for infections are crucial. Hemorrhage, including fatal and serious major hemorrhage (3% major, 0.3% fatal), has also been observed, necessitating vigilant monitoring for bleeding and consideration of dose adjustments or discontinuation if major bleeding occurs.
Cytopenias, including neutropenia (grade 3 or 4 in 26%), thrombocytopenia (grade 3 or 4 in 12%), and anemia (grade 3 or 4 in 12%), are common and require regular monitoring of complete blood counts. Cardiac arrhythmias, particularly atrial fibrillation/flutter (3.2%, with 1.5% being grade 3/4), have been reported, emphasizing the need for appropriate monitoring and management of cardiac status. Second primary malignancies, including nonmelanoma skin cancer (4.6%), developed in 9% of patients, underscoring the importance of sun protection and ongoing skin surveillance. Hepatotoxicity, including drug-induced liver injury, has also been noted, mandating baseline and ongoing evaluation of liver function tests and potential dose modifications or discontinuation.