Lilly’s Jaypirca Outperforms Imbruvica in CLL Head-to-Head Phase 3 Trial
Eli Lilly’s Jaypirca (pirtobrutinib), the first and only FDA-approved non-covalent (reversible) BTK inhibitor, has met its primary endpoint in the Phase 3 BRUIN CLL-314 trial, marking a first-of-its-kind head-to-head comparison against the standard covalent BTK inhibitor Imbruvica (ibrutinib) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), including treatment-naïve individuals.
The study demonstrated that pirtobrutinib achieved non-inferior, and nominally superior, overall response rates (ORR) compared to Imbruvica, with a P-value below 0.05, as assessed by an independent review committee. While progression-free survival (PFS) data remain immature, early trends favour Jaypirca, particularly among the treatment-naïve subgroup, which showed the most pronounced PFS effect size.
The First-ever Head-to-head Trial Versus Ibrutinib in CLL to Include Treatment-naïve Patients
This trial represents the first time a non-covalent BTK inhibitor has been directly compared to a covalent inhibitor in a Phase 3 setting with both previously treated and untreated patients, underscoring Jaypirca’s potential to reshape the treatment landscape. The drug’s safety profile remained consistent with previous studies, and no detriment to overall survival was observed. These results, alongside earlier positive data from BRUIN CLL-321 in the post-covalent BTK setting, support Jaypirca’s growing role in CLL/SLL treatment and will contribute to upcoming regulatory submissions worldwide.
Positive Topline Results from the Phase 3 BRUIN CLL-314 Clinical Trial
Eli Lilly and Company announced in a press release today positive topline results from the Phase 3 BRUIN CLL-314 clinical trial of Jaypirca (pirtobrutinib), a non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor, versus Imbruvica (ibrutinib), a covalent BTK inhibitor, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). This study enrolled patients with treatment-naïve CLL/SLL and those who had been previously treated but were BTK inhibitor-naïve. The study met its primary endpoint of non-inferiority on overall response rate (ORR) as assessed by an independent review committee (IRC) in both the pre-treated and intent-to-treat populations. ORR favored pirtobrutinib with a nominal P-value for superiority1 (p <0.05). Progression free survival (PFS), a key secondary endpoint, was not yet mature at this analysis, but was trending in favor of pirtobrutinib. A formal PFS analysis testing for superiority is planned at a future analysis. No detriment was observed for overall survival (OS).
BRUIN CLL-314 is the first ever head-to-head trial versus ibrutinib in CLL to include treatment-naïve patients. This important subpopulation (n=225) had the longest follow-up and a particularly pronounced PFS effect size in favor of pirtobrutinib.
The overall safety profile of pirtobrutinib in BRUIN CLL-314 was similar to previously reported trials. Detailed results will be presented at a medical congress later in 2025.
Jacob Van Naarden, executive vice president and president of Lilly Oncology stated:
“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. 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.”
These data build on the previously reported positive results from the BRUIN Phase 1/2 trial and the Phase 3 BRUIN CLL-321 trial, the first randomised, controlled study ever conducted in an exclusively post-covalent BTK inhibitor population. The BRUIN CLL-313 Phase 3 study of pirtobrutinib versus chemoimmunotherapy in treatment naïve CLL/SLL is expected to read out later in 2025 and combined with the results of BRUIN CLL-314, will form the basis of regulatory submissions globally. For more information on the BRUIN Phase 3 clinical trial program, please visit clinicaltrials.gov.
About the BRUIN CLL-314 Phase 3 Trial
BRUIN CLL-314 is a Phase 3, randomised, open-label study of pirtobrutinib versus ibrutinib in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who were either treatment-naïve, or who were previously treated and were BTK inhibitor-naïve. The trial planned to enroll 650 patients who were randomised 1:1 to receive pirtobrutinib (200 mg orally, once daily) or ibrutinib (420 mg orally, once daily). The primary endpoint is overall response rate (ORR) as assessed by a blinded independent review committee (IRC). Secondary endpoints include investigator and IRC assessed progression-free survival (PFS), duration of response (DoR) and event-free survival (EFS), and time to next treatment (TTNT), overall survival (OS), safety and tolerability, and patient-reported outcomes (PRO).
About Jaypirca (pirtobrutinib)
Jaypirca (pirtobrutinib, formerly known as LOXO-305) (pronounced jay-pihr-kaa) is a highly selective (300 times more selective for BTK versus 98% of other kinases tested in preclinical studies), non-covalent (reversible) inhibitor of the enzyme BTK. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).3,4 Jaypirca is a U.S. FDA-approved oral prescription medicine, 100 mg or 50 mg tablets taken as a once-daily 200 mg dose with or without food until disease progression or unacceptable toxicity.
To learn more, visit Lilly.com and Lilly.com/news
Original Source: Press Release — Eli Lilly and Company. “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.” July 29, 2025
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