RARITAN, N.J., June 12, 2021 /PRNewswire/ -- The Janssen
Pharmaceutical Companies of Johnson & Johnson today announced
primary results from the pivotal Phase 3 GLOW study (NCT03462719)
evaluating fixed-duration IMBRUVICA® plus venetoclax
(I+V) compared to chlorambucil plus obinutuzumab (Clb+O) for
first-line treatment of elderly or unfit patients with chronic
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The
study demonstrated superior progression-free survival (PFS) of a
once-daily, all-oral, fixed-duration regimen of I+V versus Clb+O as
first-line treatment of CLL; the study also showed improved
duration of remission and significantly improved depth of
remission.1 With I+V, undetectable minimal residual
disease (uMRD) in peripheral blood (PB) was sustained by 85 percent
of patients one year after end of treatment.1 The safety
and tolerability profile of I+V was consistent with CLL treatments
in an older population with comorbidities.1 These
data were featured in the European Hematology Association (EHA)
2021 Virtual Press Briefing and will be presented as a
late-breaking abstract during the EHA Virtual Congress (Abstract
#LB1902).
"In the GLOW study, two very active blood cancer treatments are
combined to create a complementary therapeutic regimen with the
hope that deep responses might enable treatment-free remission for
patients," said Arnon
Kater†, M.D., Ph.D., deputy head of hematology,
University of Amsterdam Faculty of Medicine, the Netherlands and principal study
investigator. "The data from GLOW showed that IMBRUVICA in an oral,
once-daily fixed-duration combination with venetoclax outperformed
a standard chemoimmunotherapy regimen for older or unfit patients,
providing the first comparative evidence that this approach has the
potential to improve depth of response and, therefore, extends time
to progression versus standard therapy."
The GLOW study evaluated the efficacy and safety of first-line
fixed-duration I+V versus Clb+O in elderly patients with CLL/SLL,
or patients ages 18-64 with a cumulative illness rating scale
(CIRS) score of greater than six or creatinine clearance less than
70 mL/min.1 The CIRS score measures comorbidity, or
concurrent non-CLL illness, in patients across multiple body
systems.2 GLOW excluded patients with del(17p) or
known TP53 mutations. Randomization to fixed-duration I+V or
a standard six 28-day cycle of Clb+O was stratified by
immunoglobulin heavy chain variable region gene (IgHV) mutational
status and del(11q) status.1 Patients in the I+V
arm received three months of IMBRUVICA® lead-in therapy
followed by 12 months of combination I+V therapy, and all patients
stopped therapy regardless of MRD status.1 In the
study, 106 patients received I+V and 105 received Clb+O (n=211;
median age, 71 years).1
At a median follow-up of 27.7 months, independent review
committee (IRC)-assessed PFS for fixed-duration I+V was superior to
Clb+O [Hazard Ratio (HR) 0.216; 95 percent confidence interval
[CI], 0.131-0.357; p < 0.0001] and the improvement in PFS
favoring I+V was consistent across predefined subgroups, including
older patients and patients with higher comorbidity
scores.1 Median PFS was not reached for I+V and
21.0 months for Clb+O (95 percent CI,
16.6-24.7).1 At three months after the end of
treatment (EOT+3), the rate of uMRD was significantly higher for
I+V versus Clb+O in bone marrow (51.9 percent vs. 17.1 percent,
respectively; p < 0.0001) and peripheral blood (54.7
percent versus 39.0 percent, respectively; p <
0.0001).1 Complete response (CR) rates (including
CR with incomplete hematologic recovery) by IRC assessment were
also significantly higher for fixed-duration I+V versus Clb+O (38.7
percent vs. 11.4 percent; p <
0.0001).1
Responses to fixed-duration I+V were sustained after EOT; 84.5
percent (49/58) of patients maintained peripheral blood uMRD from
EOT+3 to the assessment 12 months after EOT
(EOT+12).1 Thereby, with a median follow-up of 27.7
months, time to next anti-cancer therapy was extended with I+V vs.
Clb+O [HR, 0.143; 95 percent CI, 0.05-0.41].1
The most common Grade 3 or higher treatment-emergent adverse
events (TEAEs) for fixed-duration I+V were neutropenia/neutrophil
count decrease (34.9 percent), infections (17 percent), and
diarrhea (10.4 percent); and neutropenia/neutrophil count decrease
(49.5 percent), thrombocytopenia (20 percent), and infections (11.4
percent) for Clb+O.1 Deaths during treatment
occurred in seven patients on fixed-duration I+V and two patients
on Clb+O.1 At time of analysis, overall survival
was immature; there were eleven deaths in the fixed-duration I+V
arm and twelve in the Clb+O arm.1
Data from the Fixed-Duration Cohort of the Phase 2 CAPTIVATE
(PCYC-1142) Study of IMBRUVICA®-Based Combination
Regimen in Previously Untreated Patients with CLL (Abstract
#S147)
GLOW is part of a comprehensive development program exploring
the potential of IMBRUVICA®-based fixed-duration therapy
in previously untreated CLL. This includes the fixed-duration
cohort from the Phase 2 CAPTIVATE study in young, fit
patients that was recently presented at the 2021 American Society
of Clinical Oncology (ASCO) Annual Meeting and will also be
presented at EHA (Abstract #S147). The CAPTIVATE study evaluated
previously untreated CLL/SLL patients 70 years or younger,
including patients with high-risk disease.4 In the
fixed-duration cohort (N=159; median age, 60 years), all patients
received three months of IMBRUVICA® lead-in therapy
followed by 12 months of combination
IMBRUVICA® plus venetoclax therapy and then stopped
therapy regardless of MRD status.4 More than 90
percent of patients completed 12 cycles of
IMBRUVICA® plus venetoclax
treatment.4 At a median follow-up of 27.9 months,
the CR rate in the overall population was 56 percent (n=88; 95
percent CI, 48–64) and was consistent across high-risk
subgroups.4 Results also showed that 95 percent of
patients treated with fixed-duration I+V were alive and
progression-free at two years and deep remissions were seen across
all subgroups, including patients with high-risk
CLL.4
The safety profile of the I+V regimen in CAPTIVATE was
consistent with known safety profiles of IMBRUVICA® and
venetoclax.4 Of note, 21 percent of patients were
at risk for tumor lysis syndrome (TLS) based on high tumor burden
at baseline, and this was reduced to one percent after three cycles
of IMBRUVICA® lead-in therapy.3 AEs were
primarily Grade 1/2.4 The most common Grade 3/4 AEs
were neutropenia (33 percent), infections (eight percent),
hypertension (six percent), and neutrophil count decrease (five
percent).4 Discontinuations due to AEs were
infrequent (three percent for
IMBRUVICA®).4
"IMBRUVICA and venetoclax have complementary mechanisms of
action, and the promising results from the CAPTIVATE and GLOW
studies show that this all-oral regimen that many patients can take
at home may provide an effective, flexible treatment option for
patients with CLL/SLL seeking a fixed-duration therapy," said
Craig Tendler, M.D., Vice President,
Late Development and Global Medical Affairs, Oncology, Janssen
Research & Development, LLC. "Between these two studies, more
than 400 patients across the age and fitness spectrum of CLL
patients requiring frontline therapy have been treated with
IMBRUVICA in combination with venetoclax, further demonstrating the
potential of IMBRUVICA in this regimen across multiple patient
groups."
About IMBRUVICA®
IMBRUVICA®
(ibrutinib) is a once-daily oral medication that is jointly
developed and commercialized by Janssen Biotech, Inc. and
Pharmacyclics LLC, an AbbVie company. The BTK protein sends
important signals that tell B cells to mature and produce
antibodies. BTK signaling is needed by specific cancer cells to
multiply and spread. By blocking BTK, IMBRUVICA may help move
abnormal B cells out of their nourishing environments in the lymph
nodes, bone marrow, and other organs.4,5,6
IMBRUVICA® is approved in more than 100
countries, and, to date, is the only BTK inhibitor that has been
used to treat more than 230,000 patients worldwide.
IMBRUVICA® was first approved by the U.S. Food and
Drug Administration (FDA) in November
2013, and today is indicated for adult patients in six
disease areas, including five hematologic cancers – adults with
chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma
(SLL) with or without 17p deletion (del17p), adults with
Waldenström's macroglobulinemia (WM), adult patients with
previously treated mantle cell lymphoma (MCL)*, adult patients with
previously treated marginal zone lymphoma (MZL) who require
systemic therapy and have received at least one prior
anti-CD20-based therapy* – and adult patients with previously
treated chronic graft-versus-host disease (cGVHD) after failure of
one or more lines of systemic therapy.7
*Accelerated approval was granted for MCL and MZL based on
overall response rate. Continued approval for MCL and MZL may be
contingent upon verification and description of clinical benefit in
confirmatory trials.
IMBRUVICA® is the most comprehensively studied
BTKi, with more than 150 active clinical trials in several blood
cancers and other serious diseases. For more information, visit
www.IMBRUVICA.com.
IMBRUVICA® IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in
patients who received IMBRUVICA®. Major hemorrhage (≥
Grade 3, serious, or any central nervous system events; e.g.,
intracranial hemorrhage [including subdural hematoma],
gastrointestinal bleeding, hematuria, and postprocedural
hemorrhage) occurred in 4% of patients, with fatalities occurring
in 0.4% of 2,838 patients who received IMBRUVICA® in 27
clinical trials. Bleeding events of any grade including bruising
and petechiae occurred in 39%, and excluding bruising and petechiae
occurred in 23% of patients who received IMBRUVICA®,
respectively.
The mechanism for the bleeding events is not well
understood.
Use of either anticoagulant or antiplatelet agents concomitantly
with IMBRUVICA® increases the risk of major hemorrhage.
Across clinical trials, 3.1% of 2,838 patients who received
IMBRUVICA® without antiplatelet or anticoagulant therapy
experienced major hemorrhage. The addition of antiplatelet therapy
with or without anticoagulant therapy increased this percentage to
4.4%, and the addition of anticoagulant therapy with or without
antiplatelet therapy increased this percentage to 6.1%. Consider
the risks and benefits of anticoagulant or antiplatelet therapy
when co-administered with IMBRUVICA®. Monitor for signs
and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA®
for at least 3 to 7 days pre- and post-surgery depending upon the
type of surgery and the risk of bleeding.
Infections: Fatal and non-fatal infections (including
bacterial, viral, or fungal) have occurred with
IMBRUVICA® therapy. Grade 3 or greater infections
occurred in 21% of 1,476 patients who received
IMBRUVICA® in clinical trials. Cases of progressive
multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii
pneumonia (PJP) have occurred in patients treated with
IMBRUVICA®. Consider prophylaxis according to standard
of care in patients who are at increased risk for opportunistic
infections.
Monitor and evaluate patients for fever and infections and treat
appropriately.
Cytopenias: In 645 patients with B-cell malignancies
who received IMBRUVICA® as a single agent, grade 3 or 4
neutropenia occurred in 23% of patients, grade 3 or 4
thrombocytopenia in 8% and grade 3 or 4 anemia in 3%, based on
laboratory measurements.
Monitor complete blood counts monthly.
Cardiac Arrhythmias and Cardiac Failure: Fatal and
serious cardiac arrhythmias and cardiac failure have occurred with
IMBRUVICA®. Grade 3 or greater ventricular
tachyarrhythmias occurred in 0.2% of patients, Grade 3 or greater
atrial fibrillation and atrial flutter occurred in 4%, and Grade 3
or greater cardiac failure occurred in 1% of 1,476 patients who
received IMBRUVICA® in clinical trials. These events
have occurred particularly in patients with cardiac risk factors,
hypertension, acute infections, and a previous history of cardiac
arrhythmias.
At baseline and then periodically, monitor patients clinically
for cardiac arrhythmias and cardiac failure. Obtain an ECG for
patients who develop arrhythmic symptoms (e.g., palpitations,
lightheadedness, syncope, chest pain) or new onset dyspnea. Manage
cardiac arrhythmias and cardiac failure appropriately, and if it
persists, consider the risks and benefits of IMBRUVICA®
treatment and follow dose modification guidelines.
Hypertension: Hypertension occurred in 19% of 1,476
patients who received IMBRUVICA® in clinical trials.
Grade 3 or greater hypertension occurred in 8% of patients. Based
on data from 1,124 of these patients, the median time to onset was
5.9 months (range, 0.03 to 24 months).
Monitor blood pressure in patients treated with
IMBRUVICA® and initiate or adjust anti-hypertensive
medication throughout treatment with IMBRUVICA® as
appropriate.
Second Primary Malignancies: Other malignancies
(10%), including non-skin carcinomas (4%), occurred among the 1,476
patients who received IMBRUVICA® in clinical trials. The
most frequent second primary malignancy was non-melanoma skin
cancer (6%).
Tumor Lysis Syndrome: Tumor lysis syndrome has been
infrequently reported with IMBRUVICA®. Assess the
baseline risk (e.g., high tumor burden) and take appropriate
precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity: Based on findings in animals,
IMBRUVICA® can cause fetal harm when administered
to a pregnant woman. Advise pregnant women of the potential risk to
a fetus. Advise females of reproductive potential to use effective
contraception during treatment with IMBRUVICA® and
for 1 month after the last dose. Advise males with female partners
of reproductive potential to use effective contraception during the
same time period.
ADVERSE REACTIONS
B-cell malignancies: The most common adverse reactions
(≥30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and
MZL) were thrombocytopenia (54.5%)*, diarrhea (43.8%), fatigue
(39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%)*, rash
(35.8%), anemia (35.0%)*, and bruising (32.0%).
The most common Grade ≥ 3 adverse reactions (≥5%) in patients
with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were
neutropenia (20.7%)*, thrombocytopenia (13.6%)*, pneumonia (8.2%),
and hypertension (8.0%).
Approximately 9% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of
patients had a dose reduction due to adverse reactions.
Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL
[13%]) of patients discontinued due to adverse reactions.
cGVHD: The most common adverse reactions (≥20%) in
patients with cGVHD were fatigue (57%), bruising (40%), diarrhea
(36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis
(29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia
(21%).
The most common Grade 3 or higher adverse reactions (≥5%)
reported in patients with cGVHD were pneumonia (14%), fatigue
(12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%),
hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and
pyrexia (5%).
Twenty-four percent of patients receiving IMBRUVICA®
in the cGVHD trial discontinued treatment due to adverse reactions.
Adverse reactions leading to dose reduction occurred in 26% of
patients.
*Treatment-emergent decreases (all grades) were based on
laboratory measurements.
DRUG INTERACTIONS
CYP3A Inhibitors: Co-administration of
IMBRUVICA® with strong or moderate CYP3A inhibitors may
increase ibrutinib plasma concentrations. Dose modifications of
IMBRUVICA® may be recommended when used concomitantly
with posaconazole, voriconazole, and moderate CYP3A inhibitors.
Avoid concomitant use of other strong CYP3A inhibitors. Interrupt
IMBRUVICA® if strong inhibitors are used short-term
(e.g., for ≤ 7 days). See dose modification guidelines in USPI
sections 2.3 and 7.1.
CYP3A Inducers: Avoid coadministration with strong CYP3A
inducers.
SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria):
Avoid use of IMBRUVICA® in patients with severe hepatic
impairment. In patients with mild or moderate impairment, reduce
recommended IMBRUVICA® dose and monitor more frequently
for adverse reactions of IMBRUVICA®.
Please click here to see the full Prescribing
Information.
About the Janssen Pharmaceutical Companies of Johnson &
Johnson
At Janssen, we're creating a future where disease
is a thing of the past. We're the Pharmaceutical Companies of
Johnson & Johnson, working tirelessly to make that future a
reality for patients everywhere by fighting sickness with science,
improving access with ingenuity and healing hopelessness with
heart. We focus on areas of medicine where we can make the biggest
difference: Cardiovascular & Metabolism, Immunology, Infectious
Diseases & Vaccines, Neuroscience, Oncology and Pulmonary
Hypertension.
Learn more at www.janssen.com. Follow us at
@JanssenUS and @JanssenGlobal. Janssen
Research & Development, LLC and Janssen Biotech, Inc. are part
of the Janssen Pharmaceutical Companies of Johnson &
Johnson.
†Dr. Kater has served as a consultant to Janssen; he has not
been paid for any media work.
Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as
defined in the Private Securities Litigation Reform Act of 1995
regarding product development and the potential benefits and
treatment impact of IMBRUVICA® (ibrutinib). The reader
is cautioned not to rely on these forward-looking statements. These
statements are based on current expectations of future events. If
underlying assumptions prove inaccurate or known or unknown risks
or uncertainties materialize, actual results could vary materially
from the expectations and projections of Janssen Research &
Development, LLC, Janssen Biotech, Inc., or any of the other
Janssen Pharmaceutical Companies, and/or Johnson & Johnson.
Risks and uncertainties include, but are not limited to: challenges
and uncertainties inherent in product research and development,
including the uncertainty of clinical success and of obtaining
regulatory approvals; uncertainty of commercial success;
manufacturing difficulties and delays; competition, including
technological advances, new products and patents attained by
competitors; challenges to patents; product efficacy or safety
concerns resulting in product recalls or regulatory action; changes
in behavior and spending patterns of purchasers of health care
products and services; changes to applicable laws and regulations,
including global health care reforms; and trends toward health care
cost containment. A further list and descriptions of these risks,
uncertainties and other factors can be found in Johnson &
Johnson's Annual Report on Form 10-K for the fiscal year ended
January 3, 2021, including in the
sections captioned "Cautionary Note Regarding Forward-Looking
Statements" and "Item 1A. Risk Factors," and in the company's most
recently filed Quarterly Report on Form 10-Q, and the company's
subsequent filings with the Securities and Exchange Commission.
Copies of these filings are available online at
www.sec.gov, www.jnj.com or on request
from Johnson & Johnson. None of the Janssen Pharmaceutical
Companies nor Johnson & Johnson undertakes to update any
forward-looking statement as a result of new information or future
events or developments.
1 Kater P, et al. Fixed-Duration Ibrutinib Plus
Venetoclax (I+V) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for
First-Line Treatment of Chronic Lymphocytic Leukemia (CLL): Primary
Analysis of the Phase 3 GLOW Study. 2021 European Hematology
Association 2021 Virtual Congress. June
9-17, 2021.
2 Gribben JG. Chronic lymphocytic leukemia: planning for
an aging population. Expert Rev Anticancer Ther.
2010;10(9):1389-1394. doi:10.1586/era.10.127
3 Ghia P et al. Fixed-Duration (FD) First-Line Treatment
(tx) with Ibrutinib (I) Plus Venetoclax (V) For Chronic Lymphocytic
Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Primary Analysis
of the FD Cohort of the Phase 2 CAPTIVATE Study. 2021 American
Society of Clinical Oncology Annual Meeting. June 4-8, 2021.
4 Genetics Home Reference. Isolated growth hormone
deficiency.
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency.
Accessed June 2021.
5 Turetsky A, et al. Single cell imaging of Bruton's
tyrosine kinase using an irreversible inhibitor. Scientific
Reports. 2014;6:4782.
6 de Rooij MF, Kuil A, Geest CR, et al. The clinically
active BTK inhibitor PCI-32765 targets B-cell receptor- and
chemokine-controlled adhesion and migration in chronic lymphocytic
leukemia. Blood. 2012;119(11):2590-2594.
7 IMBRUVICA U.S. Prescribing Information, December 2020.
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