On the heels of FDA’s approval of Jaypirca (pirtobrutinib) for expanded hematologic indications last week, Eli Lilly and Company announced results from the Phase III Bruin CLL-314 trial (NCT05254743) showing Jaypirca achieved non-inferiority vs. Imbruvica (ibrutinib) with a higher response rate, reaching the study’s primary endpoint treating chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The Bruin CLL-314 trial evaluated Jaypirca in patients with CLL/SLL who were treatment-naïve or were Bruton tyrosine kinase (BTK) inhibitor-naïve, compared to Imbruvica, with data presented this weekend at the American Society of Hematology (ASH) meeting.¹

"These data from Bruin CLL-314 are both novel and clinically significant, demonstrating an improved overall response rate and a favorable trend in progression-free survival outcomes with pirtobrutinib compared to ibrutinib across all populations, including treatment-naïve patients where covalent BTK inhibitors are a cornerstone of treatment," said Jennifer A. Woyach, MD, professor, hematologist-oncologist, and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Jaypirca is approved for the treatment of adults with relapsed or refractory CLL/SLL who were previously treated with a covalent BTK inhibitor, as well as patients with relapsed or refractory mantle cell lymphoma following at least two lines of systemic therapy, including a BTK inhibitor.

Jaypirca is the first medication offering non-covalent, reversible binding, which allows greater BTK inhibition and a higher selectivity, reducing any off-target adverse effects (AEs). As a third generation BTK inhibitor, Jaypirca does not rely on binding to Cys-481 in the active site, which prevents resistance. As the body synthesizes new amounts of BTK, the drug remains in the body and causes ongoing inhibition, differing from other BTK inhibitors, which lack long half-lives, causing gaps in inhibition.²

What did the Bruin CLL-314 Phase III study evaluate?

Lilly’s Bruin CLL-314 is a randomized, open-label study comparing Jaypirca against Imbruvica in patients with CLL/SLL who were either treatment-naïve or previously treated but were BTK inhibitor-naïve.¹

The study enrolled 662 participants, who were randomly assigned in a 1:1 ratio to receive either Jaypirca or Imbruvica, orally, daily, with the participant population consisting of 225 treatment-naïve and 437 relapsed/refractory patients.¹

"Bruin CLL-314 is the first randomized study to compare covalent and non-covalent BTK inhibitors and to directly compare any BTK inhibitors in the treatment-naïve setting, offering findings that are important for advancing the field and patient care. These efficacy results, along with pirtobrutinib's safety profile, offer strong evidence on the role of pirtobrutinib earlier in the treatment course for patients with CLL or SLL," said Woyach.

Jaypirca achieves the primary endpoint of non-inferiority for overall response rate vs. Imbruvica

Jaypirca achieved the study’s primary endpoint demonstrating statistical non-inferiority compared to Imbruvica as per independent review committee (IRC)-assessed overall response rate (ORR) for the intent to treat (ITT) population.

Trial results numerically favored Jaypirca with an 87% ORR compared to 78.5% for patients administered Imbruvica.¹ Additionally, across all evaluated populations, ORR consistently favored Jaypirca over Imbruvica, including relapsed/refractory and treatment-naïve patients, along with pre-specified subgroups, such as patients with and without 17p deletions, IGHV status, and complex karyotype.¹

The trial’s secondary endpoint of progression-free survival (PFS) was not yet mature during analysis, but a formal PFS analysis testing for superiority is planned for future analysis. Collected data suggests that the trial was trending in favor of Jaypirca compared to Imbruvica in the ITT, relapsed/refractory, and treatment-naïve populations, with median follow-ups of 22 months, 18.4 months, and 22.5 months, respectively.¹

The largest PFS effect size was recorded in the treatment-naïve subgroup, which had the longest follow-up at this data cut, including a 76% reduction in the risk of disease progression or death among all subgroups.¹ 

The overall safety profile for patients treated with Jaypirca in Bruin CLL-314 remained similar to previously reported trials, with the most common treatment-emergent adverse events AEs being similar between arms.¹

Patients administered Jaypirca reported lowerAEs of interest compared to Imbruvica, including atrial fibrillation/flutter and hypertension, and fewer AE-related dose reductions were seen with Jaypirca.¹

"We are excited to share these compelling new findings for pirtobrutinib with the scientific community at American Society of Hematology and in the Journal of Clinical Oncology," said Jacob Van Naarden, executive vice president and president, Lilly Oncology. "These data build on additional results from the Bruin development program and the recent FDA approval for pirtobrutinib in the post-covalent BTK inhibitor setting to reinforce the medicine's potential to deliver meaningful benefit for people living with CLL or SLL across various disease settings."

Sources

1. Lilly's Jaypirca (pirtobrutinib) met its primary endpoint in first-of-its-kind, head-to-head Phase 3 study versus Imbruvica (ibrutinib) Eli Lilly and Company December 8, 2025 https://investor.lilly.com/news-releases/news-release-details/lillys-jaypirca-pirtobrutinib-met-its-primary-endpoint-first-its

2. Shirley M. Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features [published correction appears in Target Oncol. 2021 Dec 24;:]. Target Oncol. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8.