FDA Expands Pirtobrutinib Approval to First-Line CLL/SLL
The FDA has approved pirtobrutinib (Jaypirca) for first-line treatment of adults with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.
The FDA has approved pirtobrutinib (Jaypirca) for first-line treatment of adults with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma without 17p deletion. The agency expanded the non-covalent Bruton's tyrosine kinase inhibitor's label on Friday, marking a significant shift toward earlier use of highly effective, non-chemotherapy options.
BRUIN-CLL-313 trial demonstrates superior efficacy over chemoimmunotherapy
In the BRUIN-CLL-313 trial, pirtobrutinib reduced the risk of disease progression or death by 80% compared to bendamustine plus rituximab. The hazard ratio was 0.20 with a 95% confidence interval of 0.11-0.37 and a p-value of less than 0.0001. Median progression-free survival was not yet reached for pirtobrutinib versus 33.5 months for the chemoimmunotherapy arm.
The global, randomized, open-label Phase 3 study enrolled 282 previously untreated CLL/SLL patients without 17p deletion. They were randomized 1:1 to receive pirtobrutinib or bendamustine plus rituximab. At a median follow-up of 28 months, pirtobrutinib showed significantly improved progression-free survival.
An Independent Review Committee assessed the overall response rates. The results are shown below.
| Treatment Arm | Overall Response Rate | Complete Response Rate | Partial Response Rate |
|---|---|---|---|
| Pirtobrutinib | 94% | 13% | 81% |
| Bendamustine plus Rituximab | 81% | 21% | 60% |
Safety profile consistent with prior trials, with manageable adverse events
Pirtobrutinib showed a safety profile consistent with its established characteristics. Serious adverse reactions occurred in 28% of patients receiving the drug. The most common non-laboratory adverse events were upper respiratory tract infections (27%), rash (22%), and COVID-19 (21%).
The most common grade 3/4 laboratory abnormality was decreased neutrophil counts, occurring in 26% of patients. Adverse reactions led to dose reductions in 3.6% of patients. Permanent discontinuation of Jaypirca due to adverse reactions occurred in 4.3% of patients.
Pneumonia occurred in 5% of patients as a serious adverse reaction. Across all clinical trials, grade 3 or higher infections occurred in 23% of Jaypirca-treated patients. The drug carries warnings for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, hepatotoxicity, and embryo-fetal toxicity.
Clinical guidance and broader context for use in CLL/SLL management
Pirtobrutinib is now recommended by the National Comprehensive Cancer Network as a Category 2A option for treatment-naïve adult patients with CLL/SLL without del(17p). It is highlighted as a preferred option for older patients with cardiac comorbidities who may only need one lifetime treatment.
The drug was first approved in 2023 under an accelerated approval pathway for pretreated CLL/SLL. It is also approved for previously treated mantle cell lymphoma and has shown activity in CLL patients with Richter transformation. Jaypirca is a highly selective kinase inhibitor use a novel non-covalent binding mechanism.
Jennifer Woyach, MD, an investigator at the Ohio State University Comprehensive Cancer Center, commented on the expanded approval. "Doctors can now consider pirtobrutinib for appropriate patients when initial therapy is needed, not just later in a patient's treatment journey," she said.
Jaypirca is taken as a once-daily dose with or without food until disease progression or unacceptable toxicity. The NCCN also lists it as a Category 1 preferred option for adult patients with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor.
Eli Lilly, the drug's manufacturer, is studying Jaypirca in CLL/SLL in multiple Phase 3 studies. These include comparisons to ibrutinib and evaluations in BTK inhibitor-pretreated and venetoclax-based regimens.
