FDA Approves Pirtobrutinib for Untreated CLL/SLL Without 17p Deletion

The FDA has approved pirtobrutinib (Jaypirca; Eli Lilly) for adults with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with no known 17p deletion, according to an announcement from the agency and a news release from Eli Lilly and Company.^1,2 The decision makes the noncovalent Bruton tyrosine kinase (BTK) inhibitor available as a first-line treatment option for appropriate patients.

The expanded indication comes 10 months after the FDA granted traditional approval to pirtobrutinib for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor, converting a December 2023 accelerated approval.³

“This approval is grounded in data from BRUIN CLL-313, which showed a significant delay in disease progression for pirtobrutinib compared to chemoimmunotherapy, along with safety and tolerability consistent with its established profile,” Jennifer A. Woyach, MD, director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, said in the Eli Lilly and Company news release.²

BRUIN CLL-313 Results Support First-Line Pirtobrutinib Approval

The approval is based on the phase 3 BRUIN CLL-313 trial (NCT05023980), a randomized, open-label, active-controlled study of 282 adults with previously untreated CLL/SLL without 17p deletion.¹ Patients were randomized 1:1 to pirtobrutinib 200 mg orally once daily until disease progression or unacceptable toxicity (n = 141) or to 6 cycles of bendamustine plus rituximab (BR; n = 141). Results were published in the Journal of Clinical Oncology.⁴

With an estimated median follow-up of 28 months, the primary end point of progression-free survival (PFS) assessed by an independent review committee significantly improved with pirtobrutinib vs BR (HR, 0.20; 95% CI, 0.11-0.37; P < .0001). Median PFS was not estimable with pirtobrutinib and was 33.5 months with BR.¹ The overall response rate was 94% with pirtobrutinib and 81% with BR, although complete responses were more frequent in the BR arm (21% vs 13%).²

Overall survival data were immature at the primary PFS analysis, with median overall survival not reached in either arm; 3 patients (2.1%) receiving pirtobrutinib and 10 (7.1%) receiving BR had died.¹

Pirtobrutinib Safety Profile and Study Limitations

The most common nonlaboratory adverse reactions with pirtobrutinib were upper respiratory tract infections (27%), rash (22%), and COVID-19 (21%), and the most common grade 3 or 4 laboratory abnormality was decreased neutrophil count. Serious adverse reactions occurred in 28% of patients.¹ All-grade atrial fibrillation or flutter occurred in 1.4% of patients.² The prescribing information includes warnings for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, hepatotoxicity, and embryo-fetal toxicity.¹

Because the trial was open label and patients with significant cardiovascular disease were excluded, the low rate of atrial fibrillation may not reflect outcomes in patients with cardiac comorbidities.² In addition, 52.9% of patients with progressive disease on BR crossed over to pirtobrutinib, which could complicate survival comparisons.⁵

The National Comprehensive Cancer Network lists pirtobrutinib as a category 2A recommendation for treatment-naive adults with CLL/SLL without 17p deletion, and approximately 92% to 95% of patients diagnosed with CLL do not have a 17p deletion, according to Lilly.² Because pirtobrutinib is taken continuously until progression or unacceptable toxicity, treatment duration may also factor into payer and formulary assessments.

"Doctors can now consider pirtobrutinib for appropriate patients when initial therapy is needed, not just later in a patient's treatment journey,” Woyach said.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."

References

1. FDA approves pirtobrutinib for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. October 2, 2026. Accessed October 2, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pirtobrutinib-previously-untreated-chronic-lymphocytic-leukemia-or-small-lymphocytic

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://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non-1

3. Steinzor P. FDA grants full approval to pirtobrutinib for CLL/SLL. AJMC^®. December 3, 2025. Accessed October 2, 2026. https://www.ajmc.com/view/fda-grants-full-approval-to-pirtobrutinib-for-cll-sll

4. Jurczak W, Kwiatek M, Czyz J, et al. BRUIN CLL-313: randomized phase III trial of pirtobrutinib versus bendamustine plus rituximab in untreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2026;44(6):466-475. doi:10.1200/JCO-25-02380

5. McNulty R. Pirtobrutinib outperforms bendamustine-rituximab in frontline CLL/SLL. AJMC. December 12, 2025. Accessed October 2, 2026. https://www.ajmc.com/view/pirtobrutinib-outperforms-bendamustine-rituximab-in-frontline-cll-sll