FDA Grants Pirtobrutinib Accelerated Approval to Treat CLL/SLL in the Third Line


The FDA has approved the non-covalent BTK inhibitor, pirtobrutinib, to treat patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have already undergone 2 lines of therapy.

Pirtobrutinib (Jaypirca) has obtained accelerated approval as a treatment for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a Bruton's tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor.

Pirtobrutinib is a highly selective, non-covalent, or reversible, BTK inhibitor. Its unique mechanism of action allows it to be effective in patients who already undergone prior treatment with a BTK inhibitor.

"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 [pirtobrutinib] a meaningful advance and much-needed new treatment option for these patients," William G. Wierda, MD, PhD, professor, medical director, and CLL section head for the Department of Leukemia at The University of Texas MD Anderson Cancer Center, stated in a news release from Eli Lilly, the manufacturer of pirtobrutinib. "[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 in the BRUIN Phase 1/2 trial whose disease progressed following treatment with a covalent BTK inhibitor and with a BCL-2 inhibitor."

The BRUIN Trial

Data from the phase 1/2 BRUIN trial (NCT03740529) informed the FDA’s decision. This trial enrolled 108 patients with CLL/SLL who had been previously treated with at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. The study did not include patients who had active central nervous system (CNS) involvement or who had undergone allogeneic hematopoietic stem cell transplantation (HSCT) within 60 days.

The main end points in the trial were overall response rate (ORR) and duration of response (DOR). The ORR was 72% (95% CI, 63%-80%), with a median time to response of 3.7 months (range, 1.7-27.9). The median DOR was 12.2 months (95% CI, 9.3-14.7).

Investigators looked at a pooled analysis of the full BRUIN study population (which included disease types beyond CLL/SLL) to assess the adverse events (AEs) associated with single-agent pirtobrutinib. Overall, the most common AEs associated with treatment are decreased neutrophil count, decreased hemoglobin, fatigue, decreased lymphocyte count, musculoskeletal pain, decreased platelet count, diarrhea, COVID-19, bruising, and cough.

In the population of patients with CLL/SLL, 60% continued to receive pirtobrutinib for at least 1 year, and 14% continued for at least 2 years. The rate of AE-related dose reductions was 3.6%, the rate of interruption was 42%, and the rate of permanent discontinuation was 9%.

Of note, the median number of prior therapy lines for patients with CLL/SLL in the BRUIN trial was 5 lines (range, 2-11). Most patients had received prior ibrutinib (Imbruvica), 9% had received acalabrutinib (Calquence) , and 0.9% had received zanubrutinib (Brukinsa). Most patients (77%) discontinued prior BTK inhibitor therapy because of refractory or progressive disease.

“This FDA approval — the second for [pirtobrutinib] in 2023 — underscores the impactful clinical benefit of continuing to leverage the BTK pathway with [pirtobrutinib] for patients with CLL or SLL as seen in the BRUIN trial,” Jacob Van Naarden, chief executive officer, Loxo@Lilly, added. “These first two indications for [pirtobrutinib] represent the beginning of the eventual impact that we hope [pirtobrutinib] can have for patients, and we look forward to seeing the results of the comprehensive phase 3 development program across CLL, SLL, and MCL."


Jaypirca (pirtobrutinib) now approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed December 1, 2023. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult

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