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The FDA expanded the label of pirtobrutinib (Jaypirca) to include the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) following two prior lines of therapy, the agency announced on Friday.

An oral, non-covalent Bruton's tyrosine kinase (BTK) inhibitor, pirtobrutinib was granted accelerated approval for adults who have previously received both a BCL-2 inhibitor and a covalent BTK inhibitor, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa).

"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 Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, in a from drugmaker Eli Lilly.

Pirtobrutinib "offers a new treatment option and different approach to targeting BTK, providing clinical benefit for a high proportion of patients with CLL or SLL," added Wierda.

The single-arm phase I/II BRUIN trial provided support for the new approval. The open-label, multicohort study included 108 patients with heavily pretreated CLL/SLL (median five prior lines), with 98% having received both a BCL-2 inhibitor and a covalent BTK inhibitor and 77% refractory or progressing on their prior BTK inhibitor.

Pirtobrutinib induced partial responses in 72% (95% CI 63-80) of participants, with a median duration of response of 12.2 months (95% CI 9.3-14.7). No complete responses were observed.

Pooled safety data from patients with various hematologic malignancies in BRUIN showed that common adverse events (AEs; ≥20%) included fatigue, musculoskeletal pain, diarrhea, COVID-19, bruising, and cough, along with decreases in neutrophils, hemoglobin, lymphocytes, and platelets. Common grade 3/4 laboratory abnormalities (≥10%) included anemia and decreases in neutrophils and platelets.

Among the patients with CLL/SLL specifically, 56% experienced serious AEs while on pirtobrutinib, 3.6% required dose reductions due to AEs, and 9% permanently discontinued the drug.

Infections, hemorrhage, cytopenias, cardiac arrhythmias, embryo-fetal toxicity, and secondary malignancies are among the warnings and precautions in the drug's . In trials, serious and fatal infections occurred in 32% and 10%, respectively.

As a condition of the accelerated approval, the FDA requires that further trials demonstrate clinical benefit. To that end, Eli Lilly noted in its approval announcement that the confirmatory trial has already met its primary endpoint (progression-free survival) and that the data have now been shared with FDA. The phase III trial involves pretreated CLL/SLL patients and is testing pirtobrutinib versus investigator's choice of rituximab plus either idelalisib (Zydelig) or bendamustine (Bendeka, Treanda).

Pirtobrutinib, the first and only FDA-approved non-covalent or reversible BTK inhibitor, landed its first indication earlier this year for pretreated mantle cell lymphoma. The drug comes in 50 mg or 100 mg tablets and is taken once-daily at a 200 mg dose with or without food until progression or unacceptable toxicity.

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