Pirtobrutinib demonstrates activity across covalent BTK
inhibitor pre-treated B-cell malignancies and multiple patient
subgroups
INDIANAPOLIS, Dec. 12,
2022 /PRNewswire/ -- Loxo@Lilly, the oncology unit of
Eli Lilly and Company (NYSE: LLY), today announced updated clinical
data from the pirtobrutinib global Phase 1/2 BRUIN trial in
patients with chronic lymphocytic leukemia (CLL), small lymphocytic
lymphoma (SLL), mantle cell lymphoma (MCL), Richter transformation
(RT), and Waldenström macroglobulinemia (WM). Pirtobrutinib is an
investigational, highly selective, reversible (non-covalent)
inhibitor of Bruton's tyrosine kinase (BTK). These data are
featured in oral and poster presentations at the 2022 American
Society of Hematology (ASH) Annual Meeting.
"These data presented at ASH build on previous results with
significantly longer follow-up and continue to expand on the body
of evidence supporting pirtobrutinib as a potential treatment
option for patients previously treated with a covalent BTK
inhibitor across a range of B-cell malignancies," said Susan O'Brien, M.D., UCI Health hematology
oncologist, Chao Family Comprehensive Cancer Center and professor
of hematology/oncology at University of
California, Irvine. "For patients with CLL/SLL, MCL, and
Waldenström macroglobulinemia who have received the standard of
care regimens, including covalent BTK inhibitors, treatment options
are extremely limited. For patients with Richter transformation,
there are no standard treatment options. These results show that
pirtobrutinib may potentially help to address multiple areas of
growing unmet need."
"We continue to be very excited by the results of pirtobrutinib
across B-cell malignancies," said David
Hyman, M.D., chief medical officer, Loxo@Lilly. "These data
from the BRUIN Phase 1/2 trial provide further evidence that
pirtobrutinib's reversible binding mechanism and pharmacology may
allow for extended targeting of the BTK pathway following treatment
with a covalent BTK inhibitor. We are appreciative of the
investigators and patients involved in the BRUIN study who have
contributed to a better understanding of the potential of this
medicine."
Key Data at ASH
The BRUIN Phase 1/2 clinical trial is evaluating pirtobrutinib
monotherapy in patients previously treated for MCL, CLL/SLL, or
other non-Hodgkin lymphomas (NHL). The efficacy data being
presented at ASH for MCL and CLL/SLL are based on independent
review committee (IRC) assessment while the efficacy data for RT
and WM are based on investigator response assessments. The safety
cohort consisted of all patients with B-cell malignancies who
received at least one dose of pirtobrutinib monotherapy as of the
data cutoff date.
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma
(SLL)
The BRUIN trial includes one of the largest prospective cohorts
of BTK inhibitor pre-treated CLL/SLL patients ever studied. As of
the July 29, 2022 data cutoff date,
247 patients with CLL/SLL had received a prior BTK inhibitor and
enrolled prior to November 5, 2021,
to ensure adequate follow-up. Patients had received a median of
three prior therapies (range 1-11). In this dataset,
pirtobrutinib demonstrated an overall response rate (ORR) of 82%
(95% CI: 76.8-86.7) and median progression-free survival (PFS) of
19.6 months (95% CI: 16.9-22.1). In patients treated with both a
prior BTK and BCL2 inhibitor (n=100, median of five prior lines of
therapy), the ORR was 79% (95% CI: 69.7-86.5), and median PFS was
16.8 months (95% CI: 13.2-18.7). Response rates were consistent
across all subgroups analyzed regardless of mutation status, age,
or previous therapies.
Mantle Cell Lymphoma (MCL)
As of the January 31, 2022 data
cutoff date, the primary analysis set consisted of the first 90
patients enrolled with MCL who had received a prior BTK inhibitor.
Patients had received a median of three prior lines of therapy
(range 1-8). In this dataset, pirtobrutinib demonstrated an ORR of
58% (95% CI: 46.9-68.1), a median duration of response (DoR) of
21.6 months (95% CI: 7.5-NE) and a median PFS of 7.4 months (95%
CI: 5.3-12.5). Response rates were consistent regardless of number
of prior lines of therapy and classes of prior therapy
received.
Richter Transformation (RT)
The BRUIN trial also includes one of the largest prospective RT
populations ever studied. As of the July 29,
2022 data cutoff date, 75 patients with RT were response
evaluable, with 68 patients having received prior treatment for RT.
Among these patients, the median number of prior lines of CLL
therapy was two (range 0-11) and the median number of prior lines
of RT therapy was two (range 1-7). The ORR for the 75
response-evaluable patients was 52% (95% CI: 40.2-63.7), and for
the 68 patients previously treated for RT, the ORR was 50% (95% CI:
37.6-62.4). Among all response evaluable patients, median overall
survival (OS) was 13.1 months (95% CI: 7.8-NE) and DoR was 5.6
months (95% CI: 2.5-NE), regardless of prior RT therapy.
Waldenström Macroglobulinemia (WM)
As of the July 29, 2022 data
cutoff date, 80 patients with WM were response evaluable, with 63
patients having received prior treatment with a BTK inhibitor.
Among the 63 patients, the median number of prior therapies was
three (range 1-11). The major response rate (MRR) was 67% (95% CI:
53.7-78.0), including 15 (23.8%) very good partial responses and 27
(42.9%) partial responses. In patients who previously received both
chemoimmunotherapy and a covalent BTK inhibitor (n=50), the MRR was
68% (95% CI: 53.3-80.5). Median PFS was 19.4 months (95% CI:
15.1-22.1) in patients who received previous treatment with a
covalent BTK inhibitor (n=62).
Safety of Pirtobrutinib from the BRUIN Study
In the safety cohort of all pirtobrutinib-treated patients
(n=773), the most frequent treatment-emergent adverse events (TEAE)
(≥15%), regardless of attribution, were fatigue (29%), diarrhea
(24%), and contusion (19%). The most frequent Grade ≥3 TEAE was
neutropenia (20%). Low rates of Grade ≥3 TEAEs of hypertension
(9%), hemorrhage (11%), and atrial fibrillation/flutter (3%) were
observed. Overall, discontinuations due to a treatment-related
adverse event occurred in 3% (n=20) of all patients. The
safety profile was generally consistent across the populations
studied.
Safety and Tolerability in Covalent BTK Intolerant
Patients
The safety and tolerability of pirtobrutinib monotherapy in
patients with relapsed or refractory B-cell malignancies who were
intolerant to a prior covalent BTK inhibitor (n=127) was evaluated.
Atrial fibrillation was among the most common adverse events (AE)
that led to the discontinuation of a prior covalent BTK inhibitor,
and in these patients (n=30), this AE recurred with pirtobrutinib
treatment in two patients. Most patients did not experience
high-grade recurrence of the other common AEs that led to
discontinuation of a prior covalent BTK inhibitor, with the
exception of neutropenia (in the patients in whom neutropenia
recurred, 67% were Grade ≥3). No patient who discontinued a prior
BTK inhibitor due to an AE had to discontinue pirtobrutinib for the
same AE.
Loxo@Lilly is studying pirtobrutinib in multiple Phase 3
studies. Details on the trials can be found at
lillyloxooncologypipeline.com or by
visiting clinicaltrials.gov.
About Pirtobrutinib (LOXO-305)
Pirtobrutinib is an investigational, highly selective,
reversible (non-covalent) Bruton's tyrosine kinase (BTK) inhibitor.
BTK plays a key role in the B-cell antigen receptor signaling
pathway, which is required for the development, activation and
survival of normal white blood cells, known as B-cells, and
malignant B-cells. BTK is a validated molecular target found across
numerous B-cell leukemias and lymphomas including chronic
lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and
Waldenström macroglobulinemia (WM). Pirtobrutinib was
developed to reversibly bind BTK, deliver consistently high target
coverage regardless of BTK turnover rate, and preserve activity in
the presence of the C481 acquired resistance mutations.
Pirtobrutinib was found to be highly selective – 300 times more
selective in BTK inhibition versus 98% of other kinases tested in
preclinical studies. Interested patients and physicians can contact
the Loxo@Lilly Physician and Patient BTK Clinical Trial
Hotline at 1-855-LOXO-305 or
email clinicaltrials@loxooncology.com.
About the BRUIN Phase 1/2 Trial
The BRUIN Phase 1/2 clinical trial is the ongoing
first-in-human, global, multi-center evaluation of pirtobrutinib in
patients previously treated for mantle cell lymphoma (MCL), chronic
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or
other non-Hodgkin lymphomas (NHL).
The trial includes a Phase 1 dose-escalation phase, a Phase
1b combination arm, and a Phase 2
dose-expansion phase. The primary endpoint of the Phase 1 study is
maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D).
Secondary endpoints include safety, pharmacokinetics (PK), and
preliminary efficacy measured by overall response rate (ORR) for
monotherapy. The primary endpoint of the Phase 1b study is safety of the drug combinations. The
secondary endpoints are PK and preliminary efficacy measured by ORR
for the drug combinations. The primary endpoint for the Phase 2
study is ORR as determined by an independent review committee
(IRC). Secondary endpoints include ORR as determined by
investigator, best overall response (BOR), duration of response
(DoR), progression-free survival (PFS), overall survival (OS),
safety, and PK.
About Lilly
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Cautionary Statement Regarding Forward-Looking
Statements
This press release contains forward-looking statements (as that
term is defined in the Private Securities Litigation Reform Act of
1995) about pirtobrutinib as a potential treatment for people with
previously treated chronic lymphocytic leukemia, small lymphocytic
lymphoma, mantle cell lymphoma, Richter transformation, and
Waldenström macroglobulinemia and the timeline for future readouts,
presentations, and other milestones relating to pirtobrutinib and
its clinical trials, and reflects Lilly's current beliefs and
expectations. However, as with any pharmaceutical product, there
are substantial risks and uncertainties in the process of drug
research, development, and commercialization. Among other things,
there is no guarantee that planned or ongoing studies will be
completed as planned, that future study results will be consistent
with study results to date, that pirtobrutinib will prove to
be a safe and effective treatment for relevant indications, that
pirtobrutinib will receive regulatory approval, or that Lilly
will execute its strategy as expected. For further discussion of
these and other risks and uncertainties that could cause actual
results to differ from Lilly's expectations, see Lilly's Form 10-K
and Form 10-Q filings with the United States Securities and
Exchange Commission. Except as required by law, Lilly undertakes no
duty to update forward-looking statements to reflect events after
the date of this release.
© Lilly USA, LLC 2022. ALL
RIGHTS RESERVED.
Refer to:
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Owens_Kyle@lilly.com; 332-259-3932 –
media
Joe
Fletcher; jfletcher@lilly.com;
317-296-2884 – investors
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