FDA Approves REVLIMID® (Lenalidomide) In Combination With Rituximab For the Treatment of Adult Patients with Previously Treated Follicular Lymphoma or Marginal Zone Lymphoma

Approval marks the first chemotherapy-free combination regimen for
patients who have relapsed or did not respond to previous treatment

Approval based on Phase 3 AUGMENT study, which showed the combination
significantly improved median progression-free survival versus rituximab
monotherapy

SUMMIT, N.J.–(BUSINESS WIRE)–Celgene Corporation (NASDAQ: CELG) today announced the U.S. Food and
Drug Administration (FDA) approved REVLIMID^® (lenalidomide)
in combination with a rituximab product (R²) for the treatment of adult
patients with previously treated follicular lymphoma (FL) or marginal
zone lymphoma (MZL) following Priority Review designation. This is the
first FDA-approved combination treatment regimen for patients with these
indolent forms of non-Hodgkin’s lymphoma (NHL) that does not include
chemotherapy.

“Nearly 15 years following the initial FDA approval, REVLIMID continues
to demonstrate benefits for new patient populations,” said Jay
Backstrom, M.D., M.P.H., Chief Medical Officer for Celgene. “REVLIMID in
combination with rituximab (R²) leads to immune-mediated
treatment effects and represents a chemotherapy-free treatment option
that can help patients with previously treated follicular lymphoma and
marginal zone lymphoma delay disease progression.”

Immune dysfunction (meaning the immune system is not functioning
optimally) is a defining aspect of indolent forms of NHL, including FL
and MZL.^1,2 When this dysfunction occurs, lymphocytes in the
immune system either fail to detect or target cancerous cells.^1,2

“Chemotherapy continues to be a standard of care for indolent forms of
NHL, but most patients will relapse or become refractory to their
current treatment,” said Meghan Gutierrez, Chief Executive Officer for
the Lymphoma Research Foundation. “This approval represents a new
therapeutic option for previously treated patients with follicular and
marginal zone lymphomas, including those who relapse or no longer
respond to initial treatment. We commend the patients and scientists who
participated in the clinical study for advancing lymphoma research and
treatment.”

The approval of R² is based primarily on results from the
randomized, double-blind, Phase 3 AUGMENT study, which evaluated the
efficacy and safety of the R² combination versus rituximab plus placebo
in patients with previously treated FL (n=295) and MZL (n=63).

In the AUGMENT study, treatment with R² demonstrated a
statistically significant improvement in the primary endpoint of
progression-free survival (PFS), evaluated by an independent review
committee, versus rituximab-placebo. The median PFS was 39.4 months for
patients treated with R² and 14.1 months for those treated
with rituximab-placebo (HR: 0.46; 95% CI, 0.34-0.62; P<0.0001). Median
follow-up time was 28.3 months (range, 0.1-51.3) in the intent to treat
population (n=358). Although not statistically powered to detect a
difference in overall survival, a numeric trend for improvement in
overall survival (a secondary endpoint) was also seen with R²
versus rituximab-placebo (16 vs. 26 deaths) (HR: 0.61; 95% CI,
0.33-1.13).

REVLIMID is only available through a restricted distribution program
called REVLIMID REMS^® program. REVLIMID has a boxed warning
for embryo-fetal toxicity, hematologic toxicity, and venous and arterial
thromboembolism. Adverse reactions reported in ≥15% of patients with
FL/MZL treated with R² were: neutropenia (58%), diarrhea
(31%), constipation (26%), cough (24%), fatigue (22%), rash (22%),
pyrexia (21%), leukopenia (20%), pruritus (20%), upper respiratory tract
infections (18%), abdominal pain (18%), anemia (16%), headache (15%),
thrombocytopenia (15%).

A Marketing Authorization Application for R² is currently
under review by the European Medicines Agency for the treatment of
relapsed/refractory FL and MZL. A supplemental new drug application was
also submitted to the Japanese Pharmaceuticals and Medical Devices
Agency for an additional indication as well as dosage and administration
updates for lenalidomide in combination with rituximab for the treatment
of relapsed/refractory indolent B-cell NHL.

About Indolent Lymphoma

Lymphoma is a blood cancer that develops in lymphocytes, a type of white
blood cell in the immune system that helps protect the body from
infection.³ There are two classes of lymphoma – Hodgkin’s
lymphoma and non-Hodgkin’s lymphoma (NHL) – each with specific subtypes
that determine how the cancer behaves, spreads and should be treated.^3,4,5

Indolent lymphomas are slow-growing forms of the disease, which can
often be asymptomatic or have fewer symptoms upon diagnosis.⁶
Indolent lymphomas account for approximately 40% of all NHL cases.⁶
In patients with relapsed/refractory lymphoma, the disease has either
responded to treatment but then returned or has not responded to initial
treatment.⁷

About AUGMENT

AUGMENT is a Phase 3, randomized, double-blind clinical trial evaluating
the efficacy and safety of REVLIMID^® (lenalidomide) in
combination with rituximab (R²) versus rituximab plus placebo in
patients with previously treated follicular lymphoma and marginal zone
lymphoma. AUGMENT included patients diagnosed with Grade 1, 2 or 3a
follicular lymphoma, who received at least 1 prior systemic therapy,
were refractory or relapsed, not rituximab-refractory.

The primary endpoint was progression-free survival, defined as the time
from date of randomization to the first observation of disease
progression or death due to any cause. Secondary and exploratory
endpoints included overall response rate, durable complete response
rate, complete response rate, duration of response, duration of complete
response, overall survival, event-free survival and time to next
anti-lymphoma therapy.

About REVLIMID^®

REVLIMID^® (lenalidomide) in combination with
dexamethasone (dex) is indicated for the treatment of adult patients
with multiple myeloma (MM)

REVLIMID is indicated as maintenance therapy in adult patients with
MM following autologous hematopoietic stem cell transplantation
(auto-HSCT)

REVLIMID is indicated for the treatment of adult 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 adult patients with mantle
cell lymphoma (MCL) whose disease has relapsed or progressed after two
prior therapies, one of which included bortezomib

REVLIMID in combination with a rituximab product is indicated for the
treatment of adult patients with previously treated follicular lymphoma
(FL)

REVLIMID in combination with a rituximab product is indicated for the
treatment of adult patients with previously treated marginal zone
lymphoma (MZL)

REVLIMID is not indicated and is not recommended for the treatment of
patients with chronic lymphocytic leukemia (CLL) outside of controlled
clinical trials

REVLIMID is only available through a restricted distribution program,
REVLIMID REMS^®.

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. Patients may require dose interruption and/or dose reduction. MM:
Monitor complete blood counts (CBC) in patients taking REVLIMID +
dexamethasone or REVLIMID as maintenance therapy, every 7 days for the
first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days
thereafter. MDS: Monitor CBC
in patients on therapy for del 5q MDS, weekly for the first 8
weeks of therapy and at least monthly thereafter. See Boxed WARNINGS
for further information. MCL:
Monitor CBC in patients taking REVLIMID for MCL weekly for the first
cycle (28 days), every 2 weeks during cycles 2-4, and then monthly
thereafter. FL/MZL: Monitor
CBC in patients taking REVLIMID for FL or MZL weekly for the first 3
weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then
monthly thereafter

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 the 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 and in patients with FL or MZLreceiving
REVLIMID + rituximab therapy, an increase of hematologic plus solid
tumor SPM, notably AML, have been observed. In MM patients, MDS was also
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 MM, the addition of pembrolizumab to a thalidomide
analogue plus dexamethasone resulted in increased mortality. Treatment
of patients with MM 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 + dexamethasone. 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. 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 REVLIMID. The patients at risk of TLS are
those with high tumor burden prior to treatment. Closely monitor
patients at risk and take appropriate preventive approaches

Tumor Flare Reaction (TFR): TFR has occurred during
investigational use of REVLIMID for CLL and lymphoma. Monitoring and
evaluation for TFR is recommended in patients with MCL, FL, or MZL.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 starting 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%)

Follicular Lymphoma/Marginal Zone Lymphoma

• Fatal adverse reactions occurred in 6 patients (1.5%) receiving
  REVLIMID + rituximab across both trials. Fatal adverse reactions (1
  each) included: cardio-respiratory arrest, arrhythmia, cardiopulmonary
  failure, multiple organ dysfunction syndrome, sepsis, and acute kidney
  injury. The most frequent serious adverse reaction that occurred in
  the REVLIMID/rituximab arm was

febrile neutropenia (3.0%).

• Grade 3 and 4 adverse reactions reported in ≥5% of patients treated in
  the FL/MZL trial with REVLIMID + rituximab were: neutropenia (50%) and
  leukopenia (7%)
• Adverse reactions reported in ≥15% of patients with FL/MZL treated
  with REVLIMID + rituximab were: neutropenia (58%), diarrhea (31%),
  constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia
  (21%), leukopenia (20%), pruritus (20%), upper respiratory tract
  infections (18%), abdominal pain (18%), anemia (16%), headache (15%),
  thrombocytopenia (15%)

DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to increased C_max 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 dexamethasone
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
• 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, for REVLIMID.

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.
Follow Celgene on Social Media: @Celgene,
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Contacts

For Celgene:
Investors:
908-673-9628
[email protected]

Media:
908-673-2275
[email protected]

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