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Lilly and Company announced results from the Phase 3 BRUIN CLL-322 clinical
trial of Jaypirca (pirtobrutinib), a non-covalent Bruton tyrosine kinase (BTK)
inhibitor, plus venetoclax and rituximab versus venetoclax and rituximab in
patients with relapsed or refractory chronic lymphocytic leukemia or small
lymphocytic lymphoma (CLL/SLL).
The study met its primary endpoint of independent review committee
(IRC)-assessed progression-free survival (PFS), demonstrating that the addition
of pirtobrutinib to a two-year venetoclax plus rituximab regimen reduced the
risk of disease progression or death by 45%.
These data will be highlighted in a late-breaking oral presentation at the 2026
European Hematology Association (EHA) Annual Meeting taking place in Stockholm,
Sweden, as well as featured in the meeting's press program.
"These results from BRUIN CLL-322 show that the addition of pirtobrutinib
as part of a time-limited regimen further enhanced an already effective
treatment and extended the duration of remission for patients with previously
treated CLL. Importantly, the study provides the first robust evidence for such
an approach in patients who received a prior BTK inhibitor," said Matthew
S. Davids, M.D., M.M.Sc., Chief of the Division of Lymphoma at Dana-Farber
Cancer Institute, who is the lead author on the study.
"Time-limited regimens are an important option in CLL care and provide
patients with meaningful treatment-free intervals. In the context of the modern
CLL treatment landscape, where many patients may only receive two lines of
therapy, these results speak to the potential benefits that improving
second-line therapy can have. Our study has the potential to establish a new
standard of care in this population."
BRUIN CLL-322 enrolled 639 relapsed or refractory patients, with 79.8% having
prior covalent BTK inhibitor exposure, who were randomized 1:1 to receive
pirtobrutinib plus venetoclax and rituximab (PVR, n=321) or venetoclax and
rituximab alone (VR, n=318). Patients in the PVR arm received three cycles of
pirtobrutinib and the first three cycles of rituximab before venetoclax was
introduced.
The efficacy results are based on a February 2, 2026 data cutoff. At a median
follow-up of 27.3 months, the primary endpoint of IRC-assessed PFS was
significantly improved with the addition of pirtobrutinib to VR compared to VR
alone (HR=0.55 [95% CI, 0.40-0.75]; p=0.0001). Median PFS in the PVR arm was
not reached (95% CI, 43.3-NE), versus 39.7 months (95% CI, 35.9-NE) in the VR
arm.
The PFS results were consistent across prespecified subgroups, including
patients with prior covalent BTK inhibitor exposure (PVR: not reached [95% CI,
41.5-NE] versus VR: 36.2 months [95% CI, 33.2-NE]), those who discontinued
prior covalent BTK inhibitor due to progressive disease (PVR: 43.3 months [95%
CI, 39.2-NE] versus VR: 33.2 months [95% CI, 28.3-37.5]), as well as those with
high-risk features such as unmutated IGHV, TP53 mutation and/or 17p deletion,
and/or complex karyotype. In an exploratory analysis of second-line patients
whose disease progressed after a first-line covalent BTK inhibitor, the median
PFS was not reached (95% CI, 30.1-NE) in the PVR arm and was 28.3 months (95%
CI, 20.5-NE) in the VR arm (HR=0.32 [95% CI, 0.14-0.73]), with 24-month PFS
rates of 88% (95% CI, 75.7-94.6) and 52% (95% CI, 34.7-66.2), respectively, and
consistent benefit was observed regardless of the specific prior covalent BTK
inhibitor received, said the company.
Overall survival (OS), a key secondary endpoint, was not yet mature at this
analysis (HR=0.89 [95% CI, 0.57-1.40]), and final testing of OS superiority is
planned at a future date. An additional secondary endpoint, time to next
treatment (TTNT), consistently favored the pirtobrutinib combination regimen.
The overall safety profile of this regimen in BRUIN CLL-322 was consistent with
the known safety profile of each medicine, with little additive toxicity
observed with the addition of pirtobrutinib to venetoclax and rituximab. Rates
of Grade =3 adverse events (AEs) were similar with PVR compared to VR (78.8%
versus 73.0%, respectively). Low rates of any grade atrial fibrillation/flutter
(3.5% versus 2.6%, respectively), hypertension (12.0% versus 7.4%,
respectively), and hemorrhage (14.2% versus 10.6%, respectively) were seen with
PVR versus VR.
Grade =3 clinical AEs of interest included neutropenia (50.3% versus 43.7%,
respectively) and tumor lysis syndrome (0.9% versus 3.9%, respectively) in the
PVR and VR arms. Discontinuation rates due to treatment-related AEs were
similar across the PVR and VR study arms (5.4% versus 5.1%, respectively). The
addition of pirtobrutinib to VR also allowed for downgrading of tumor lysis
risk, with 78% of high-risk patients downgraded to medium (n=20) or low risk
(n=18), and 61% of medium-risk patients downgraded to low risk.
"These remarkable findings support the potential addition of two years of
Jaypirca to a time-limited venetoclax-based regimen in relapsed or refractory
CLL," said Jacob Van Naarden, executive vice president and president of
Lilly Oncology.
"BRUIN CLL-322 enrolled a mostly covalent BTK inhibitor-pretreated
population, ensuring that these results have applicability to the modern CLL
treatment landscape where covalent BTK inhibitor use is now common.
Additionally, these data further strengthen the unique body of evidence for
Jaypirca across the CLL continuum, from monotherapy to combination therapy and
across multiple settings where CLL patients need effective treatment."
Lilly plans to submit results from the BRUIN CLL-322 study to global regulatory
authorities with the goal of further expanding Jaypirca's label. The company is
studying Jaypirca in CLL/SLL in multiple Phase 3 studies.
