ORLANDO, Fla., Dec. 7, 2019 /PRNewswire/ -- The Janssen
Pharmaceutical Companies of Johnson & Johnson today announced
combination data from two studies and a long-term integrated
analysis evaluating the use of IMBRUVICA®
(ibrutinib) for the treatment of previously untreated patients with
CLL or small lymphocytic lymphoma (SLL). Results from a 48-month
follow-up analysis of the Phase 3 E1912 clinical study reported a
statistically significant difference in PFS and OS for
IMBRUVICA® plus rituximab compared to a
standard chemoimmunotherapy regimen of fludarabine,
cyclophosphamide and rituximab (FCR). Further, the latest
integrated analysis from the Phase 3 RESONATE™
(PCYC-1112) and RESONATE™-2 (PCYC-1115/1116) studies
investigating the use of single-agent
IMBRUVICA® in CLL, reported that at up to
six years of follow-up, PFS, OS and response rates improved when
IMBRUVICA® was used in earlier lines of
therapy. During this extended follow-up,
IMBRUVICA® was tolerated across all lines
of therapy with 19 percent of patients discontinuing due to adverse
events.
In addition, results presented from the Phase 2 CAPTIVATE study
suggest that patients who received
IMBRUVICA® plus venetoclax as a
time-limited treatment achieved high rates of uMRD in peripheral
blood (75 percent of patients) and bone marrow (72 percent of
patients).
These new findings from the E1912,
RESONATE™/RESONATE™-2 and CAPTIVATE
studies were presented at the 2019 American Society of
Hematology (ASH) Annual Meeting.
"We're pleased to see follow-up results from the Phase 3 E1912
trial, where the investigational use of IMBRUVICA plus rituximab is
shown to extend OS for previously untreated patients with CLL. In
addition, with the integrated analysis of the Phase 3 RESONATE and
RESONATE-2 studies, IMBRUVICA demonstrated an OS benefit in
untreated and relapsed patients with improved outcomes in early
lines of therapy," said Craig Tendler, M.D., Vice President,
Clinical Development and Global Medical Affairs, Oncology, Janssen
Research & Development, LLC. "We are also excited to see the
first MRD data from the fixed-duration regimen of IMBRUVICA plus
venetoclax in the Phase 2 CAPTIVATE trial, reporting a high rate of
undetectable MRD at 15 months both in the peripheral blood and bone
marrow."
E1912 extended follow-up of investigational use of
IMBRUVICA® plus rituximab compared to FCR
in patients with CLL/SLL ages 70 or younger (Abstract
#33)
Longer-term outcomes data from the Phase 3 E1912 clinical trial
– designed and conducted by the ECOG-ACRIN Cancer Research Group
(ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI),
part of the National Institutes of Health – were also presented. As
previously reported in earlier data readouts, the study evaluated
354 previously untreated patients with CLL ages 70 years or younger
who were randomly assigned to receive
IMBRUVICA® and rituximab or six courses of
intravenous FCR every 28 days.
At a median follow-up of 48 months, 73 percent of patients in
the IMBRUVICA® plus rituximab treatment arm
remained on IMBRUVICA® with median time on
treatment of 43 months. PFS benefits were observed for the
IMBRUVICA® plus rituximab arm as compared
to the FCR treatment arm (hazard ratio [HR], 0.39; 95 percent
confidence interval [CI], 0.26-0.57; p<0.0001). OS benefit also
continued to favor the IMBRUVICA® plus
rituximab arm (HR, 0.34; 95 percent CI, 0.15-0.79; p=0.009).
Grade 3 and above treatment-related adverse events (AEs) were
observed in 70 percent of patients in the
IMBRUVICA® plus rituximab arm versus 80
percent in the FCR arm (odds ratio [OR], 0.56; 95 percent CI,
0.34-0.90; p=0.013).
The E1912 study served as the basis of the
recent supplemental New Drug Application to the U.S. Food and
Drug Administration (FDA) to expand the
IMBRUVICA® label to include the combination
with rituximab for the first-line treatment of patients with CLL or
SLL. The submission is being reviewed by the FDA under the
Real-Time Oncology Review (RTOR) pilot program.
MRD cohort of the Phase 2 CAPTIVATE study on
IMBRUVICA® plus venetoclax combination in
patients with previously untreated CLL/SLL (Abstract
#35)
The Phase 2 CAPTIVATE (PCYC-1142) clinical trial
evaluated 164 patients younger than 70 years (median age of 58
years) with previously untreated CLL/SLL. Patients received
IMBRUVICA® monotherapy as lead-in
treatment for three cycles, followed by 12 cycles of
IMBRUVICA® plus venetoclax combination
therapy. MRD status was evaluated in peripheral blood (PB)
after six, nine, and 12 cycles and in bone marrow (BM) after 12
cycles of IMBRUVICA® plus
venetoclax.
"The new results from the CAPTIVATE study demonstrated the
all-oral regimen of ibrutinib monotherapy followed by combined
ibrutinib and venetoclax achieved promising rates of undetectable
minimal residual disease, an important indicator of deep response,
in previously untreated patients with CLL," said Constantine Tam, M.D., Hematologist and Disease
Group Lead, Low Grade Lymphoma and CLL, Peter MacCallum Cancer
Centre, Victoria, Australia, and
principal study investigator. "We look forward to continuing to
explore the efficacy and safety profile of this regimen and its
potential to provide a limited-duration option in first-line
treatment of CLL."
Results showed undetectable MRD (uMRD) – defined as less than
one CLL cell per 10,000 leukocytes (MRD<0.01 percent) by flow
cytometry– was achieved at any time after baseline in PB for 75
percent of patients (122 of 163 patients) and in BM for 72 percent
(111 of 155 patients). The high rates of uMRD in BM were consistent
across high-risk subgroups, including in patients with del(17p);
del(17p) or TP53 mutation; del(11q); complex karyotype; and
unmutated IGHV status. In patients with uMRD in PB with
matched BM samples, 93 percent of patients had uMRD in both PB and
BM. With median follow-up of 14.7 months, three patients (2
percent) experienced disease progression.
The most common AEs of any grade (in 20 percent of patients or
greater) were diarrhea (31 percent) and arthralgia (22 percent)
during treatment with IMBRUVICA® alone; and diarrhea (60
percent), neutropenia (40 percent), nausea (34 percent), upper
respiratory tract infection (24 percent), and fatigue (20 percent)
during treatment with IMBRUVICA® plus venetoclax. AEs
leading to dose reductions occurred in 20 percent of patients
overall. AEs leading to discontinuation were infrequent, occurring
in 7 percent of patients overall (IMBRUVICA®: 5 percent;
venetoclax: 4 percent).
Results from the MRD-guided, randomized treatment
discontinuation cohort and fixed-duration cohort of the CAPTIVATE
clinical trial are being further evaluated and will be presented at
a future medical meeting.
About IMBRUVICA®
IMBRUVICA® is a once-daily, first-in-class
Bruton's tyrosine kinase (BTK) inhibitor that is administered
orally, and is jointly developed and commercialized by Janssen
Biotech, Inc. and Pharmacyclics LLC, an AbbVie
company. IMBRUVICA® blocks the BTK
protein; 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.1,2 By
blocking BTK, IMBRUVICA® may help move
abnormal B cells out of their nourishing environments in the lymph
nodes, bone marrow, and other organs.3
IMBRUVICA® is the most comprehensively
studied molecule in the class with more than 150 ongoing clinical
trials and four Phase 3 studies supporting the U.S. label. It is
approved in more than 95 countries for at least one indication, and
to date, has been used to treat more than 170,000 patients
worldwide across approved indications. It was first approved
by the U.S. Food and Drug Administration (FDA) in November 2013, and today is indicated in six
disease areas, including five hematologic cancers – chronic
lymphocytic leukemia (CLL) with or without 17p deletion (del17p);
small lymphocytic lymphoma (SLL) with or without del17p;
Waldenström's macroglobulinemia (WM); previously-treated patients
with mantle cell lymphoma (MCL)*; previously-treated patients with
marginal zone lymphoma (MZL) who require systemic therapy and have
received at least one prior anti-CD20-based therapy*; and
previously-treated patients with chronic graft-versus-host disease
(cGVHD) after failure of one or more lines of systemic
therapy.4
* 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.
As of early 2019, the National Comprehensive Cancer
Network® (NCCN®), a
not-for-profit alliance of 28 leading cancer centers devoted to
patient care, research, and education, recommends ibrutinib
(IMBRUVICA®) as a preferred regimen for the
initial treatment of CLL/SLL, and it is the only Category 1
single-agent regimen for treatment-naïve patients without deletion
17p. IMBRUVICA® is the only
FDA-approved medicine in WM and cGVHD.
IMBRUVICA® has been granted four
Breakthrough Therapy Designations by the FDA, and it was one of the
first medicines to receive U.S. approval with the Breakthrough
Therapy Designation.
For more information, visit www.IMBRUVICA.com.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in
patients treated with IMBRUVICA®. Major
hemorrhage (≥ Grade 3, serious, or any central nervous system
events; e.g., intracranial hemorrhage [including subdural
hematoma], gastrointestinal bleeding, hematuria, and post
procedural hemorrhage) have occurred in 4% of patients, with
fatalities occurring in 0.4% of 2,838 patients exposed to
IMBRUVICA® in 27 clinical trials. Bleeding
events of any grade, including bruising and petechiae, occurred in
39% of patients treated with
IMBRUVICA®.
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. In IMBRUVICA® clinical trials,
3.1% of patients taking 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 24% of 1,124 patients exposed to
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: Treatment-emergent Grade 3 or 4
cytopenias including neutropenia (23%), thrombocytopenia (8%), and
anemia (3%) based on laboratory measurements occurred in patients
with B-cell malignancies treated with single agent
IMBRUVICA®.
Monitor complete blood counts monthly.
Cardiac Arrhythmias: Fatal and serious cardiac
arrhythmias have occurred with IMBRUVICA®
therapy. Grade 3 or greater ventricular tachyarrhythmias occurred
in 0.2% of patients, and Grade 3 or greater atrial fibrillation and
atrial flutter occurred in 4% of 1,124 patients exposed to
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.
Periodically monitor patients clinically for cardiac
arrhythmias. Obtain an ECG for patients who develop arrhythmic
symptoms (e.g., palpitations, lightheadedness, syncope, chest pain)
or new onset dyspnea. Manage cardiac arrhythmias appropriately, and
if it persists, consider the risks and benefits of
IMBRUVICA® treatment and follow dose
modification guidelines.
Hypertension: Hypertension of any grade occurred in
12% of 1,124 patients treated with
IMBRUVICA® in clinical trials. Grade 3 or
greater hypertension occurred in 5% of patients with a median time
to onset of 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%) have occurred in 1,124
patients treated with 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®
therapy. 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 women to avoid becoming
pregnant while taking IMBRUVICA® and for 1
month after cessation of therapy. If this drug is used during
pregnancy or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to a
fetus. Advise men to avoid fathering a child during the same time
period.
ADVERSE REACTIONS
B-cell malignancies: The most common adverse
reactions (≥20%) in patients with B-cell malignancies (MCL,
CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%),
anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash
(32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage
(24%), and pyrexia (20%).
The most common Grade 3 or 4 adverse reactions (≥5%) in patients
with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were
neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia
(14%).
Approximately 7% (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 2.4 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 baseline hepatic impairment. In patients with mild or
moderate impairment, reduce IMBRUVICA®
dose.
Please click here for 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
www.twitter.com/JanssenGlobal and www.twitter.com/JanssenUS.
Janssen Research & Development, LLC and Janssen Biotech, Inc.
are part of the Janssen Pharmaceutical Companies of Johnson &
Johnson.
Cautions Concerning Forward-Looking Statements
This
press release contains "forward-looking statements" as defined in
the Private Securities Litigation Reform Act of 1995 regarding
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, 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 December
30, 2018, 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 Genetics Home Reference. Isolated growth
hormone deficiency.
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency.
Accessed December 2019.
2 Turetsky, A, et al. Single cell imaging of Bruton's
tyrosine kinase using an irreversible inhibitor. Scientific
Reports. 2014;6:4782.
3 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.
4 IMBRUVICA U.S. Prescribing Information,
September 2019.
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