FDA Approves Pirtobrutinib For Treatment of Adult Patients With CLL, SLL


Pirtobrutinib is the first and only non-covalent BTK inhibitor to be approved by the FDA and is indicated for adult patients who already received at least 2 prior lines of therapy.

The FDA has approved 50 mg and 100 mg tablets of pirtobrutinib (Jaypirca; Eli Lilly and Company) for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least 2 prior lines of therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor. Continued approval for this indication may be subject upon verification and description of clinical benefit in a confirmatory trial.

The approval is a result of an FDA Accelerated Approval pathway that was based on overall response rate (ORR) and duration of response (DOR) from the open-label, single-arm, multicohort, phase 1/2 BRUIN trial. Pirtobrutinib is the first and only non-covalent BTK inhibitor to be approved by the FDA. It is a highly selective kinase inhibitor that can extend the benefit of targeting the BTK pathway in CLL/SLL patients who were previously treated with a covalent BTK inhibitor (eg, ibrutinib, acalabrutinib, or zanubrutinib) and a BCL-2 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," said 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, in a press release. "[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 FDA approval is based on data from the BRUIN phase 1/2 trial which assessed the efficacy of pirtobrutinib in 108 patients with CLL/SLL who were previously treated with at least 2 lines of therapy including a BTK inhibitor—most common were ibrutinib, acalabrutinib, and zanubrutinib—and a BCL-2 inhibitor. Efficacy was established based on ORR and DOR. Further, patients in the efficacy-eligible cohort had received a median of 5 prior lines of therapy (range: 2 to 11 therapies). Patients received a 200 mg dose of pirtobrutinib daily, continuing until disease progression or unacceptable toxicity. Approximately 60% were exposed to pirtobrutinib for at least 1 year, and 14% were exposed for at least 2 years.

The trial included a phase 1 dose-escalation phase, a phase 1b combination arm, and a phase 2 dose-expansion phase. The primary endpoints were maximum tolerated dose for phase 1, safety of drug combinations for phase 1b, and ORR as determined by an independent review committee in for phase 2. Secondary endpoints were safety, pharmacokinetics (PK) and preliminary efficacy measured by ORR in phase 1, PK and preliminary efficacy measured by ORR in phase 1b, and ORR as determined by investigator, best overall response, DOR, progression-free survival, overall survival, safety, and PK for phase 2.

"This FDA approval—the second for [pirtobrutinib] in 2023—underscores the impactful clinical benefit of continuing to leverage the BTK pathway with Jaypirca for patients with CLL or SLL as seen in the BRUIN trial," said Jacob Van Naarden, chief executive officer, Loxo@Lilly, in the press release. "These first 2 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 mantel cell lymphoma."

In the study population, the most common adverse effects (AEs) to pirtobrutinib therapy that occurred in 20% of patients or more included laboratory abnormalities, decreased neutrophil count, decreased hemoglobin, fatigue, decreased lymphocyte count, musculoskeletal pain, decreased platelet count, diarrhea, COVID-19, bruising, and cough. Serious AEs occurred in approximately 56% of patients who received pirtobrutinib, including pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Additional AEs for pirtobrutinib include infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, and embryo-fetal toxicity.

"The treatment landscape for CLL has been dramatically improved by the introduction of covalent BTK inhibitors and BCL-2 inhibitors. However, most patients will unfortunately relapse eventually," said Brian Koffman, MD, chief medical officer and executive vice president at the CLL Society, in the press release. "Pirtobrutinib's approval gives patients a much-needed option and brings forward new possibilities as they continue their treatment journey."


Eli Lilly and Company. 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. December 1, 2023. Accessed December 4, 2023. https://prnmedia.prnewswire.com/news-releases/jaypirca-pirtobrutinib-now-approved-by-us-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--302003695.html

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