SUMMIT, N.J. -Monday 3 December 2018 [ AETOS Wire ]
Pivotal phase 3 data show investigational R2 significantly
extended progression-free survival compared with rituximab plus placebo
Positive trend in overall survival was observed
Regulatory submissions planned for Q1 2019
(BUSINESS
WIRE)-- Celgene Corporation (NASDAQ: CELG) today announced results
of the phase 3 AUGMENT study, which showed that REVLIMID® (lenalidomide)
in combination with rituximab (R2) demonstrated superior
progression-free survival (PFS) in patients with relapsed/refractory indolent
lymphoma compared to patients who received rituximab plus placebo (R-placebo).
The data were presented by John Leonard, M.D. in an oral presentation at the 60th American
Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, C.A.
(Abstract #445).
The
phase 3 randomized, double-blind, international clinical study evaluated the efficacy
and safety of the investigational combination of R2 versus
rituximab plus placebo in patients (n=358) with relapsed/refractory follicular
(n=295) and marginal zone (n=63) lymphoma.
In
the study, the R2 arm demonstrated a highly statistically
significant improvement in the primary endpoint of progression-free survival
(PFS), evaluated by an independent review committee, versus (vs.) the R-placebo
arm. The median PFS was 39.4 months for patients treated with R2 and
14.1 months for those treated with R-placebo (P <0.0001; HR: 0.46; 95% CI,
0.34-0.62).
“The
AUGMENT data, with R2 more than doubling progression-free
survival over rituximab monotherapy, represents an important potential new
treatment option for patients with relapsed/refractory follicular or marginal
zone lymphoma,” said John Leonard, M.D., AUGMENT lead investigator, The Richard
T. Silver Distinguished Professor of Hematology and Medical Oncology and
director of the Joint Clinical Trials Office at Weill Cornell Medicine, who has
also served as a consultant for Celgene.
Overall
survival (OS), a secondary endpoint, showed a positive trend for improvement in
the R2 arm vs. the control arm (16 vs. 26 death events) (HR:
0.61; 95% CI, 0.33-1.13). Two-year OS rate was 93% for patients receiving R2 and
87% for those receiving R-placebo.
Overall
response rate (ORR), another secondary endpoint, was 78% (n=138) in the R2 arm
vs. 53% (n=96) in the R-placebo arm, according to the independent review
committee. Duration of response (DoR) was significantly improved for R2 vs.
R-placebo with median DoR of 37 vs. 22 months, respectively (P =0.0015; HR:
0.53; 95% CI, 0.36-0.79).
The
most frequent adverse event (AE) in the R2 arm was neutropenia
(58%), vs. 22% in the R-placebo arm. Additional commonly observed AEs in more
than 20% of patients included diarrhea (31% in the R2 arm vs.
23% in R-placebo), constipation (26% vs. 14%, respectively), cough (23% vs.
17%), and fatigue (22% vs. 18%), respectively. Adverse events that were
reported at a higher rate (>10%) in the R2 arm were
neutropenia, constipation, leukopenia, anemia, thrombocytopenia and tumor
flare. No unexpected safety findings were observed in the AUGMENT trial.
“These
data represent a potential new treatment strategy for patients with
relapsed/refractory indolent non-Hodgkin’s lymphomas,” said Alise Reicin, M.D.,
President, Global Clinical Development for Celgene. “We are advancing
regulatory submissions in the first quarter of 2019 to bring this important combination
to patients as soon as possible.”
REVLIMID® alone
or in combination with other agents is not approved for use in follicular
lymphoma or marginal zone lymphoma in any geography.
About REVLIMID®
REVLIMID® (lenalidomide) in combination with
dexamethasone (dex) is indicated for the treatment of patients with multiple
myeloma (MM)
REVLIMID is indicated as maintenance therapy in patients
with MM following autologous hematopoietic stem cell transplantation
(auto-HSCT)
REVLIMID® is indicated for the treatment of
patients with transfusion-dependent anemia due to low-or intermediate-1–risk
myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic
abnormality with or without additional cytogenetic abnormalities
REVLIMID® is indicated for the treatment of
patients with mantle cell lymphoma (MCL) whose disease has relapsed or
progressed after two prior therapies, one of which included bortezomib
REVLIMID is not indicated and is not recommended for the
treatment of patients with chronic lymphocytic leukemia (CLL) outside of
controlled clinical trials
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and
VENOUS and ARTERIAL THROMBOEMBOLISM
Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide
analogue, caused limb abnormalities in a developmental monkey study.
Thalidomide is a known human teratogen that causes severe life-threatening
human birth defects. If lenalidomide is used during pregnancy, it may cause
birth defects or embryo-fetal death. In females of reproductive potential,
obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females
of reproductive potential must use 2 forms of contraception or continuously
abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment.
To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available
through a restricted distribution program, the REVLIMID REMS® program.
Information about the REVLIMID REMS® program
is available at www.celgeneriskmanagement.com or
by calling the manufacturer’s toll-free number 1-888-423-5436.
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and
thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose
delay/reduction during the major study. Thirty-four percent of patients had to
have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen
in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS
should have their complete blood counts monitored weekly for the first 8 weeks
of therapy and at least monthly thereafter. Patients may require dose
interruption and/or reduction. Patients may require use of blood product
support and/or growth factors.
Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of
deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of
myocardial infarction and stroke in patients with MM who were treated with
REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs
and symptoms of thromboembolism. Advise patients to seek immediate medical care
if they develop symptoms such as shortness of breath, chest pain, or arm or leg
swelling. Thromboprophylaxis is recommended and the choice of regimen should be
based on an assessment of the patient’s underlying risks.
CONTRAINDICATIONS
Pregnancy: REVLIMID
can cause fetal harm when administered to a pregnant female and is
contraindicated in females who are pregnant. 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 risk to the fetus
Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have
demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson
syndrome, toxic epidermal necrolysis) to lenalidomide
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: See Boxed WARNINGS
·
Females of Reproductive
Potential: See Boxed WARNINGS
· Males: Lenalidomide is present in
the semen of patients receiving the drug. Males must always use a latex or
synthetic condom during any sexual contact with females of reproductive
potential while taking REVLIMID and for up to 4 weeks after discontinuing
REVLIMID, even if they have undergone a successful vasectomy. Male patients
taking REVLIMID must not donate sperm
· Blood Donation: Patients must not
donate blood during treatment with REVLIMID and for 4 weeks following
discontinuation of the drug because the blood might be given to a pregnant
female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS® Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the
REVLIMID REMS program by enrolling and complying with the REMS requirements;
pharmacies must only dispense to patients who are authorized to receive
REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with
REMS requirements; female patients of reproductive potential who are not
pregnant must comply with the pregnancy testing and contraception requirements
and males must comply with contraception requirements
Hematologic Toxicity: REVLIMID can cause significant neutropenia and
thrombocytopenia. Monitor patients with neutropenia for signs of
infection. Advise patients to observe for bleeding or bruising, especially with
use of concomitant medications that may increase risk of bleeding. MM: Patients
taking REVLIMID/dex or REVLIMID as maintenance therapy should have their
complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on
days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients
on therapy for del 5q MDS should have their complete blood counts monitored
weekly for the first 8 weeks of therapy and at least monthly thereafter.
Patients may require dose interruption and/or dose reduction. Please see
the Black Box WARNINGS for further information. MCL: Patients
taking REVLIMID for MCL should have their CBCs monitored weekly for the first
cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter.
Patients may require dose interruption and/or dose reduction
Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial
thromboses (MI and CVA) are increased in patients treated with REVLIMID.
Patients with known risk factors, including prior thrombosis, may be at greater
risk and actions should be taken to try to minimize all modifiable factors
(e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is
recommended and the regimen should be based on patient’s underlying risks. ESAs
and estrogens may further increase the risk of thrombosis and their use should
be based on a benefit-risk decision
Increased Mortality in Patients with CLL: In a clinical trial in the first-line treatment of patients
with CLL, single agent REVLIMID therapy increased the risk of death as compared
to single agent chlorambucil. Serious adverse cardiovascular reactions,
including atrial fibrillation, myocardial infarction, and cardiac failure,
occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not
recommended for use in CLL outside of controlled clinical trials
Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving
REVLIMID, an increase of hematologic plus solid tumor SPM, notably AML and MDS,
have been observed. Monitor patients for the development of SPM. Take into
account both the potential benefit of REVLIMID and risk of SPM when considering
treatment
Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma,
the addition of pembrolizumab to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of patients with multiple myeloma
with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide
analogue plus dexamethasone is not recommended outside of controlled clinical
trials
Hepatotoxicity: Hepatic
failure, including fatal cases, has occurred in patients treated with
REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver
enzymes, and concomitant medications may be risk factors. Monitor liver enzymes
periodically. Stop REVLIMID upon elevation of liver enzymes. After return to
baseline values, treatment at a lower dose may be considered
Severe Cutaneous Reactions Including Hypersensitivity
Reactions: Angioedema and severe cutaneous
reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis
(TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have
been reported. DRESS may present with a cutaneous reaction (such as rash, or
exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with
systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis,
and/or pericarditis. These events can be fatal. Patients with a prior history
of Grade 4 rash associated with thalidomide treatment should not receive
REVLIMID. REVLIMID interruption or discontinuation should be considered for
Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4
rash, exfoliative or bullous rash, or if SJS, TEN, or DRESS is suspected and
should not be resumed following discontinuation for these reactions
Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during
treatment with lenalidomide. The patients at risk of TLS are those with high
tumor burden prior to treatment. These patients should be monitored closely and
appropriate precautions taken
Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide
for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in
patients with MCL. Tumor flare may mimic the progression of disease (PD). In
patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with
REVLIMID until TFR resolves to ≤Grade 1. REVLIMID may be continued in patients
with Grade 1 and 2 TFR without interruption or modification, at the physician’s
discretion
Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected
after treatment (>4 cycles) with REVLIMID has been reported. Consider early
referral to transplant center to optimize timing of the stem cell collection
Thyroid Disorders: Both
hypothyroidism and hyperthyroidism have been reported. Measure thyroid function
before start of REVLIMID treatment and during therapy
Early Mortality in Patients with MCL: In another MCL study, there was an increase in early deaths
(within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm.
Risk factors for early deaths include high tumor burden, MIPI score at
diagnosis, and high WBC at baseline (≥10 x 109/L)
ADVERSE REACTIONS
Multiple Myeloma
·
In newly
diagnosed: The most frequently reported
Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia,
pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract,
lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency
of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%).
There were more Grade 3 and 4 and serious adverse reactions of infection in Arm
Rd Continuous than either Arm MPT or Rd18
·
The most common adverse reactions
reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia
(35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash
(26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%),
abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
·
Maintenance
Therapy Post Auto-HSCT: The most
frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included
neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of
lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm
·
The most frequently reported adverse
reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1,
Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia
(23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%),
bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%),
gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%),
asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
·
After at least
one prior therapy: The most common adverse
reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%),
neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%),
muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%),
peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%),
upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness
(23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs
7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes
·
Grade 3 and 4 adverse events
reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%),
thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia
(5%), fatigue (5%), dyspnea (5%), and back pain (5%)
·
Adverse events reported in ≥15% of
del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%),
diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%),
nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain
(21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%),
muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia
(15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma
·
Grade 3 and 4 adverse events
reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134)
included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia
(9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile
neutropenia (6%)
·
Adverse events reported in ≥15% of
patients treated with REVLIMID in the MCL trial included neutropenia (49%),
thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea
(30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%),
peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS
Periodic
monitoring of digoxin plasma levels is recommended due to increased Cmax and
AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies
such as erythropoietin stimulating agents or estrogen containing therapies may
have an increased risk of thrombosis. It is not known whether there is an
interaction between dex and warfarin. Close monitoring of PT and INR is
recommended in patients with MM taking concomitant warfarin
USE IN SPECIFIC POPULATIONS
·
PREGNANCY: See
Boxed WARNINGS: If pregnancy does occur during
treatment, immediately discontinue the drug and refer patient to an
obstetrician/gynecologist experienced in reproductive toxicity for further
evaluation and counseling. There is a REVLIMID pregnancy exposure registry that
monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as
well as female partners of male patients who are exposed to REVLIMID. This
registry is also used to understand the root cause for the pregnancy. Report
any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at
1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436
·
LACTATION: There is no information regarding the presence of
lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or
the effects of REVLIMID on milk production. Because many drugs are excreted in
human milk and because of the potential for adverse reactions in breastfed
infants from REVLIMID, advise female patients not to breastfeed during
treatment with REVLIMID
·
PEDIATRIC
USE: Safety and effectiveness have not
been established in pediatric patients
·
RENAL
IMPAIRMENT: Adjust the starting dose of REVLIMID
based on the creatinine clearance value and in patients on dialysis
Please see full Prescribing
Information, including Boxed WARNINGS.
About Celgene
Celgene
Corporation, headquartered in Summit, New Jersey, is an integrated global
biopharmaceutical company engaged primarily in the discovery, development and
commercialization of innovative therapies for the treatment of cancer and
inflammatory diseases through next-generation solutions in protein homeostasis,
immuno-oncology, epigenetics, immunology and neuro-inflammation. For more
information, please visit www.celgene.com.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements,
which are generally statements that are not historical facts. Forward-looking
statements can be identified by the words "expects,"
"anticipates," "believes," "intends,"
"estimates," "plans," "will," "outlook"
and similar expressions. Forward-looking statements are based on management's
current plans, estimates, assumptions and projections, and speak only as of the
date they are made. Celgene undertakes no obligation to update any
forward-looking statement in light of new information or future events, except
as otherwise required by law. Forward-looking statements involve inherent risks
and uncertainties, most of which are difficult to predict and are generally
beyond our control. Actual results or outcomes may differ materially from those
implied by the forward-looking statements as a result of the impact of a number
of factors, many of which are discussed in more detail in Celgene's Annual
Report on Form 10-K and other reports filed with the Securities and Exchange
Commission.
Hyperlinks are provided as a convenience and for
informational purposes only. Celgene bears no responsibility for the security
or content of external websites.
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