FDA Expands First-Line Approval of Non-Covalent BTK Inhibitor Pirtobrutinib for CLL/SLL

The FDA expanded approval of pirtobrutinib (Jaypirca) for first-line use in adults with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) lacking known 17p deletions.

This authorization for the non-covalent Bruton’s tyrosine kinase (BTK) inhibitor rests on the randomized BRUIN-CLL-313 trial, which demonstrated an 80% reduction in disease progression or death compared with chemoimmunotherapy.

Median progression-free survival was not estimable with pirtobrutinib versus 33.5 months with bendamustine plus rituximab (HR 0.20, 95% CI 0.11-0.37, P<0.0001). Overall response rates reached 94% for pirtobrutinib versus 81% for bendamustine plus rituximab.

“Clinicians can now consider pirtobrutinib for appropriate patients when initial therapy is required, rather than reserving it for later lines,” said investigator Jennifer Woyach, MD, of the Ohio State University Comprehensive Cancer Center, in an Eli Lilly press release. “Given the efficacy and tolerability of modern targeted therapies — along with factors such as age or comorbidities — many patients diagnosed with CLL or SLL today may receive only one or two treatment regimens, underscoring the importance of optimal first-line choices.”

Originally approved in 2023 under accelerated approval for pretreated CLL/SLL, pirtobrutinib has also shown activity in Richter transformation and is approved for previously treated mantle cell lymphoma. It remains the only non-covalent BTK inhibitor authorized in the U.S.

The open-label BRUIN-CLL-313 trial confirmed that pirtobrutinib’s safety profile remained “consistent with its established profile,” Woyach added.

In randomized studies, the most frequent non-laboratory adverse events with pirtobrutinib were upper respiratory tract infections (27%), rash (22%), and COVID-19 (21%). Decreased neutrophil counts (26%) were the most common grade 3/4 laboratory abnormality, and serious adverse events occurred in 28% of patients.

Prescribing information includes warnings for infections, hemorrhage, cytopenias, cardiac arrhythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.

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