Pirtobrutinib Gains FDA Approval for Frontline CLL/SLL in Select Patients

The FDA has approved pirtobrutinib (Jaypirca) for the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with no known 17p deletion, expanding the agent’s indication into the frontline setting for a defined population of adult patients.^1,2

The approval is based on findings from the phase 3 BRUIN CLL-313 trial (NCT05023980), which demonstrated a significant progression-free survival (PFS) benefit with pirtobrutinib compared with bendamustine plus rituximab (Rituxan). At a median follow-up of 28 months, median PFS was not reached with pirtobrutinib compared with 33.5 months with bendamustine plus rituximab. Pirtobrutinib reduced the risk of disease progression or death by 80% (HR, 0.20; 95% CI, 0.11-0.37; P <.0001).

The overall response rate (ORR) was 94% (95% CI, 89%-98%) with pirtobrutinib, including complete and partial response rates of 13% and 81%, respectively, compared with an ORR of 81% (95% CI, 73%-87%), complete response rate of 21%, and partial response rate of 60% with bendamustine plus rituximab. Overall survival (OS) data were immature at the primary PFS analysis.

"Doctors can now consider pirtobrutinib for appropriate patients when initial therapy is needed, not just later in a patient's treatment journey," Jennifer A. Woyach, MD, hematologist-oncologist and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, stated in a news release.² "Given the efficacy and tolerability of modern targeted therapies—coupled with factors like age or comorbidity—many people diagnosed with CLL or SLL today may only receive [1] or [2] lines of therapy, making initial treatment choices critically important."

Pirtobrutinib: Background and Approval History

Pirtobrutinib is a highly selective, noncovalent Bruton tyrosine kinase (BTK) inhibitor that binds reversibly to BTK. The agent was initially granted accelerated approval by the FDA in December 2023 for adults with CLL or SLL who had received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.³ The indication was subsequently converted to traditional approval in December 2025 for adults with CLL or SLL previously treated with a covalent BTK inhibitor.⁴

About BRUIN CLL-313

BRUIN CLL-313 was a randomized, open-label, active-controlled phase 3 trial that enrolled 282 patients with previously untreated CLL/SLL without 17p deletion.⁵ Patients were randomly assigned 1:1 to pirtobrutinib (n = 141), administered continuously until disease progression or unacceptable toxicity, or bendamustine plus rituximab (n = 141) for 6 cycles. PFS assessed by an independent review committee was the primary end point; secondary end points included OS, investigator-assessed PFS, safety, and tolerability.

Safety Profile

In BRUIN CLL-313, the most common nonlaboratory adverse reactions occurring in at least 20% of patients receiving pirtobrutinib were upper respiratory tract infection (27%), rash (22%), and COVID-19, including COVID-19 pneumonia (21%). Serious adverse reactions occurred in 28% of patients. Adverse reactions led to dose reductions in 3.6% of patients and permanent treatment discontinuation in 4.3%. Atrial fibrillation or flutter occurred in 1.4% of patients.

The recommended dose of pirtobrutinib for the newly approved indication is 200 mg orally once daily until disease progression or unacceptable toxicity. The prescribing information includes warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrhythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.

REFERENCES

1. FDA approves pirtobrutinib for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. US Food and Drug Administration. October 2, 2026. Accessed October 2, 2026. https://tinyurl.com/4a9w4nmc

2. Lilly's Jaypirca (pirtobrutinib), the first-and-only approved non-covalent BTK inhibitor, receives expanded indication from U.S. FDA for certain patients with previously untreated CLL/SLL. News release. Eli Lilly and Company. October 2, 2026. Accessed October 2, 2026. https://tinyurl.com/bdf3rpz7

3. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic leukemia. News release. US Food and Drug Administration. December 1, 2023. Accessed October 2, 2026. https://tinyurl.com/44nzmehd

4. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. US Food and Drug Administration. Published December 3, 2025. Accessed October 2, 2026. https://tinyurl.com/sxt9t3ps

5. A Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients With Chronic Lymphocytic Leukemia (CLL)/​Small Lymphocytic Lymphoma (SLL) (BRUIN-CLL-313). ClinicalTrials.gov. Updated September 25, 2026. Accessed October 2, 2026. https://clinicaltrials.gov/study/NCT05023980