Pirtobrutinib Demonstrates ORR Noninferiority vs Ibrutinib in BTK Inhibitor–Naive CLL/SLL

According to topline findings from the phase 3 BRUIN CLL-314 trial (NCT05254743), pirtobrutinib (Jaypirca) met the study’s primary end point of overall response rate (ORR) noninferiority compared with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1

In the intent-to-treat population, which comprised patients with treatment-naive CLL/SLL as well as those who had been previously treated but were Bruton tyrosine kinase [BTK] inhibitor–naive, the ORR favored pirtobrutinib over ibrutinib (nominal P < .05). Although PFS data were immature at the time of analysis, the effect size for progression-free survival (PFS) was particularly pronounced in favor of pirtobrutinib in the treatment‑naive subset (n = 225), which had the longest follow-up. No detriment to overall survival (OS) was observed.

"These data mark the second positive phase 3 study in the program, as we continue to build evidence supporting the potential role of pirtobrutinib in treating people with CLL/SLL and hopefully enabling future regulatory approvals that allow physicians to use the medicine in various disease settings, whether treatment-naïve or BTK inhibitor-pretreated,” Jacob Van Naarden, executive vice president and president of Lilly Oncology, explained in a news release.

The safety profile of pirtobrutinib in BRUIN CLL-314 was consistent with prior trials, including the phase 3 BRUIN CLL‑321 (NCT04666038) and the phase 1/2 BRUIN study (NCT03740529). Detailed ORR, PFS, and safety results will be presented at a medical congress in late 2025, with additional data from the phase 3 BRUIN CLL‑313 trial (NCT05023980) expected later in 2025 to support global regulatory submissions.

BRUIN CLL-314 Trial Design and Enrollment Criteria

The BRUIN CLL‑314 trial is an ongoing, multicenter, randomized, open‑label phase 3 study designed to evaluate the efficacy and safety of pirtobrutinib compared with ibrutinib in patients with CLL/SLL who are either treatment‑naive or were previously treated but have not been exposed to BTK inhibition.2

The trial enrolled patients with confirmed CLL/SLL requiring therapy per International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. In part 1, patients were required to have known 17p deletion status (wild type or deleted); in part 2, patients were required to have a confirmed 17p deletion by fluorescence in situ hybridization.3

Eligible participants needed an ECOG performance status of 0 to 2 and adequate organ function, including as follows:

• Platelet count of at least 50 × 10⁹/L (or at least 30 × 10⁹/L if bone marrow involvement impaired hematopoiesis)
• Hemoglobin of at least 8 g/dL (or at least 6 g/dL with marrow impairment)
• Absolute neutrophil count of at least 0.75 × 10⁹/L (or at least 0.50 × 10⁹/L with marrow impairment)
• Estimated creatinine clearance of at least 30 mL/min

Patients were excluded from the trial if they had known or suspected Richter transformation to diffuse large B‑cell lymphoma, prolymphocytic leukemia, or Hodgkin lymphoma at any time prior to enrollment. Additional exclusion criteria included known or suspected central nervous system involvement and a significant history of renal, neurologic, psychiatric, endocrine, metabolic, or immunologic disease. Patients were also excluded if they had the following:

• Active, uncontrolled autoimmune cytopenia (eg, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura)
• Significant cardiovascular disease, including left ventricular ejection fraction <40% or any grade of ongoing atrial fibrillation or atrial flutter
• Active or ongoing hepatitis B or hepatitis C infection, as indicated by screening laboratory tests
• Active cytomegalovirus infection or uncontrolled systemic bacterial, viral, or fungal infection or HIV infection
• Clinically significant malabsorption syndrome or other condition likely to impair gastrointestinal absorption of orally administered study treatments
• Ongoing inflammatory bowel disease
• Previous treatment for CLL/SLL with a BTK inhibitor (covalent or noncovalent)

Approximately 650 patients were randomly assigned 1:1 to receive either pirtobrutinib at 200 mg orally once daily or ibrutinib at 420 mg orally once daily.1 Treatment in both arms was administered continuously in 28‑day cycles until disease progression or unacceptable toxicity. 1

The primary end point of the trial was ORR, as assessed by blinded independent review committee (IRC). 1,3 Key secondary end points include investigator‑ and IRC‑assessed PFS, duration of response, event‑free survival, time to next treatment, overall survival, safety and tolerability, and changes in patient‑reported outcomes from baseline.

References

1. Lilly's Jaypirca (pirtobrutinib), the first and only approved non-covalent (reversible) BTK inhibitor, met its primary endpoint in a head-to-head Phase 3 trial versus Imbruvica (ibrutinib) in CLL/SLL. News release. Eli Lilly. July 29, 2025. Accessed July 29, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non
2. Woyach JA, Wierda WG, Coombs CC, et al. BRUIN CLL-314: a phase III open-label, randomized study of pirtobrutinib (LOXO-305) versus ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2022;140(suppl 1):12427-12428. doi:10.1182/blood-2022-157589
3. A study of pirtobrutinib (LOXO-305) versus ibrutinib in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (BRUIN-CLL-314). ClinicalTrials.gov. Updated July 16, 2025. Accessed July 29, 2025. https://www.clinicaltrials.gov/study/NCT05254743