Pirtobrutinib Outperforms Ibrutinib in Head-to-Head Phase 3 Trial for CLL/SLL

Pirtobrutinib (Jaypirca; Eli Lilly) met its primary end point of overall response rate (ORR) in a head-to-head phase 3 trial compared with ibrutinib (Imbruvica; Janssen Biotech, Inc) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL). Additionally, although immature, the progression-free survival (PFS) data trended favorably, suggesting pirtobrutinib’s potential efficacy in this treatment setting.

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Pirtobrutinib, formerly known as LOXO-305, is an oral, highly selective, noncovalent inhibitor of the enzyme Bruton tyrosine kinase (BTK), a molecular target found across numerous B-cell malignancies, including mantle cell lymphoma (MCL) and CLL/SLL. In 2023, it received accelerated approval from the FDA for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor. The decision was based on data from the BRUIN trial (NCT03740529), which showed a 72% ORR and 12.2-month duration of response (DOR) in patients treated with pirtobrutinib.^1-3

To further elucidate pirtobrutinib’s efficacy and safety, it was set up in a head-to-head study against ibrutinib—the first BTK inhibitor to receive FDA approval, leading to sweeping changes in the CLL/SLL treatment landscape. Notably, this trial is the first-ever head-to-head phase 3 study to include treatment-naive patients (n = 225).^1,4

BRUIN CLL-314 (NCT05254743) is a randomized, open-label study investigating pirtobrutinib vs ibrutinib treatment in patients with CLL/SLL who were either treatment-naive or who were previously treated and were BTK inhibitor-naive. The patients (n = 650) were randomly assigned 1:1 to receive pirtobrutinib at a dosage of 200 mg orally once daily or ibrutinib at a dosage of 420 mg orally once daily. The primary end point is ORR, with key secondary end points including PFS, DOR, event-free survival, time to next treatment, overall survival, safety, and tolerability.^1,5

"We launched the pirtobrutinib randomized development program with an ambitious suite of clinical trials, including head-to-head studies against modern standards of care and examinations of patient populations that reflect real-world use, such as BTK inhibitor-pretreated patients," Jacob Van Naarden, executive vice president and president of Lilly Oncology, said in a press release. "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-naive or BTK inhibitor-pretreated."¹

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. Eli Lilly. July 29, 2025. Accessed July 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-first-and-only-approved-non

2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 1, 2023. Accessed July 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

3. A study of oral LOXO-305 in patients with previously treated CLL/​SLL or NHL. Updated June 4, 2025. Accessed July 29, 2025. https://clinicaltrials.gov/study/NCT03740529

4. Gerlach A. Real-world study supports ibrutinib dose reduction for managing adverse events in CLL. Pharmacy Times^®. March 18, 2025. Accessed July 31, 2025. https://www.pharmacytimes.com/view/real-world-study-supports-ibrutinib-dose-reduction-for-managing-adverse-events-in-cll

5. A study of pirtobrutinib (LOXO-305) versus ibrutinib in participants with chronic lymphocytic leukemia (CLL)/​small lymphocytic lymphoma (SLL) (BRUIN-CLL-314). Updated July 31, 2025. Accessed July 321, 2025. https://clinicaltrials.gov/study/NCT05254743