Eli Lilly and Company has announced highly positive results from the Phase 3 BRUIN CLL-314 trial, demonstrating that its drug, Jaypirca (pirtobrutinib), met its primary endpoint in a head-to-head comparison against the current standard-of-care, Imbruvica (ibrutinib). The study, which is the first-ever randomized trial comparing a non-covalent BTK inhibitor with a covalent BTK inhibitor, showed that Jaypirca achieved non-inferiority on the Overall Response Rate (ORR) and exhibited numerically superior efficacy and a favorable safety profile in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
Trial Design and Patient Population
The BRUIN CLL-314 trial is a Phase 3, randomized, open-label study designed to compare Jaypirca (pirtobrutinib), a highly selective, non-covalent (reversible) Bruton tyrosine kinase (BTK) inhibitor, with Imbruvica (ibrutinib), a covalent BTK inhibitor.
- Target Disease: Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL).
- Participants: The study enrolled 662 patients who were either treatment-naïve or previously treated but BTK inhibitor-naïve (meaning they had not yet received a BTK inhibitor).
- Primary Endpoint: Overall Response Rate (ORR) as assessed by an independent review committee (IRC).
- Key Secondary Endpoints: Progression-Free Survival (PFS) and overall safety.
Key Efficacy Results
The results showed that Jaypirca was not only non-inferior to Imbruvica but also numerically superior in key efficacy measures:
Overall Response Rate (ORR)
- Jaypirca achieved the primary endpoint by demonstrating statistical non-inferiority for IRC-assessed ORR in the intent-to-treat (ITT) population (p < 0.0001).
- The results numerically favored Jaypirca with an ORR of 87.0% compared to 78.5% for Imbruvica.
- The higher ORR was consistent across all evaluated patient subgroups, including those with high-risk disease features like 17p deletions, IGHV status, and complex karyotype.
Progression-Free Survival (PFS)
- PFS data, a key secondary endpoint, were immature at the time of this analysis but showed a significant trend in favor of Jaypirca over Imbruvica in the ITT population.
- The most pronounced effect was observed in the treatment-naïve subgroup, which had the longest follow-up. In this group, Jaypirca showed a 76% reduction in the risk of disease progression or death.
Read More: Eli Lilly Announces Positive Results from Two Phase 3 Studies of Jaypirca at ASH 2025
Safety and Tolerability Profile
The overall safety profile of Jaypirca in the BRUIN CLL-314 trial was consistent with previous reports, highlighting a significant advantage over Imbruvica in managing adverse events (AEs) of clinical interest.
| Adverse Event of Interest | Jaypirca (pirtobrutinib) Rate | Imbruvica (ibrutinib) Rate |
| Atrial Fibrillation/Flutter | 2.4% | 13.5% |
| Hypertension | 10.6% | 15.1% |
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Clinical Significance and Future Outlook
These trial results represent a major advance in the treatment landscape for CLL/SLL. The BRUIN CLL-314 study is the first randomized data to directly compare a covalent and a non-covalent BTK inhibitor, providing strong evidence for using a non-covalent inhibitor in earlier lines of therapy.
The findings are expected to reinforce Jaypirca’s potential to offer meaningful benefit to a broader range of patients with CLL/SLL, whether they are newly diagnosed (treatment-naïve) or have previously relapsed. Lilly intends to use these data to support future global regulatory submissions for the earlier use of Jaypirca.
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