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Results of Phase III RELEVANCE Study Comparing REVLIMID plus Rituximab (R2) Versus Rituximab Plus Chemotherapy in Patients with Previously Untreated Follicular Lymphoma to be Presented at ASCO 2018

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Celgene Corporation (NASDAQ:CELG) today announced additional results
from RELEVANCE, a phase III, randomized, open-label, international
clinical study conducted in partnership with the Lymphoma Academic
Research Organisation (LYSARC), were presented at the 54th
Annual American Society of Clinical Oncology Scientific Sessions (ASCO)
in Chicago, Illinois on June 1-5, 2018.

This investigational study evaluated REVLIMID® (lenalidomide)
plus rituximab (R2), followed by R2 maintenance,
an investigational regimen, compared to the standard of care treatment
of rituximab plus chemotherapy (R-chemo: R-CHOP, R-bendamustine or
R-CVP) followed by rituximab maintenance in patients with previously
untreated follicular lymphoma. Investigators found that treatment with a
chemotherapy-free R2 regimen offered numerically similar
efficacy results for the primary endpoints of progression free survival
(PFS) and complete response or unconfirmed complete response (CR/CRu) at
120 weeks with a different safety profile than treatment with the
conventional R-chemo standard. As previously disclosed, the study did
not achieve the primary endpoints of superior PFS and CR/CRu.

"These findings provide important insight into the efficacy and safety
of a chemotherapy-free regimen in patients with previously untreated
follicular lymphoma and represent an important step forward in
understanding possible treatment options for these patients," said
Nathan Fowler, MD, Associate Professor, Department of Lymphoma/Myeloma,
University of Texas MD Anderson Cancer Center.

The co-primary efficacy endpoints of the study were CR and CRu at 120
weeks and PFS during the pre-planned analysis (final analysis of CR/CRu
and interim analysis of PFS). An analysis of the findings found that 48%
of patients in the R2 arm and 53% of those receiving R-chemo
maintained CR/Cru 120 weeks after randomization, with a 3-year estimated
interim PFS rate of 77% and 78% respectively (P=0.48, HR (95% CI) 1.10
(0.85-1.43)). Preliminary overall survival, one of the study's secondary
endpoints, showed a 3-year survival rate of 94% in both treatment arms.
Other secondary endpoints included number of patients with adverse
events, time to treatment failure, event-free survival, time to next
anti-lymphoma treatment, time to next chemotherapy treatment, overall
response rate at 120 weeks based on International Working Group (IWG)
1999 criteria, and health-related quality of life as measured by the
EORTC QLQ-C30.

The majority of patients in both arms completed treatment (69% R2
and 71% R-chemo). The most common Grade 3/4 TEAEs in both arms were
neutropenia (32% R2 vs. 50% R-chemo), febrile neutropenia (2%
R2 vs. 7% R-chemo) and cutaneous events (7% R2 vs.
1% R-chemo). SPMs were reported in 7% R2 and 10% R-chemo
patients, and Grade 5 AEs were 1% in both treatment arms.

"We believe the findings of the RELEVANCE trial add further to the
understanding of the R2 regimen in patients with follicular
lymphoma," said Nadim Ahmed, President of Hematology and Oncology for
Celgene. "We now look forward to the results of our AUGMENT study, which
is evaluating this important regimen in previously treated patients with
indolent lymphomas. These studies support our ongoing efforts to develop
a portfolio of novel treatments for lymphoma."

REVLIMID alone or in combination with rituximab is not approved for use
in follicular lymphoma in any country.

ABOUT RELEVANCE

RELEVANCE is the first multi-center, international, open-label,
randomized phase III clinical trial of the chemotherapy-free combination
immunotherapy R2 vs. R-chemo followed by rituximab
maintenance in previously untreated, advanced follicular lymphoma
patients. The study was conducted by Celgene in the US and Japan and by
LYSARC in the rest of the world at 136 centers in 10 countries and
evaluated the safety and efficacy of REVLIMID plus rituximab (R2)
followed by R2 maintenance compared to the standard of care
treatment of rituximab plus chemotherapy (R-CHOP, R-bendamustine or
R-CVP) followed by rituximab maintenance.

The trial evaluated 1030 patients with advanced follicular lymphoma who
had not received prior treatment and were deemed to require treatment
per Groupe d'Etude des Lymphomes Folliculaires (GELF) Criteria. Patients
received treatment for 120 weeks and were randomized to receive either R2
or R-chemo treatment. The median age of the patients was 59 years.

The R2 arm received REVLIMID + Rituximab on the following
dosing schedules: REVLIMID 20-mg on days 2-22 every 28 days for up to 6
cycles. Patients with a complete response after 6 cycles then received
REVLIMID 10-mg on days 2-22 every 28 days for 12 cycles. Patients with a
partial response after 6 cycles continued to receive REVLIMID 20 mg for
3-6 cycles until they achieved a CR/CRu, at which time they then
received REVLIMID 10 mg on days 2-22 of every 28-day cycle for up to 9
or 6 cycles, respectively. Patients who remained in partial response
after the additional 6 cycles received REVLIMID 10 mg for a total of 18
cycles. Rituximab 375 mg/m2 was administered on days 1, 8, 15
and 22 of cycle 1, day 1 of cycles 2 to 6; 8 weeks later responding
patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.

The R-chemo arm received ONE of the following: Rituximab – CHOP (72%),
Rituximab – CVP (5%), or Rituximab – Bendamustine (23%). Seven to 8
weeks later, responding patients continued with 375 mg/m2
rituximab every 8 weeks for 12 cycles.

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.
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About LYSARC

The Lymphoma Academic Research Organisation (LYSARC), located in Lyon,
France, is an academic clinical research organization running
international clinical lymphoma trials in affiliation with the LYSA and
in collaboration with other renowned, international cooperative groups.
For more information, please visit www.lysarc.org.

About LYSA

The Lymphoma Study Association (LYSA), is a French association leader in
international clinical and translational research in lymphoma, with a
network of 130 centers in France, Switzerland, Portugal and Belgium. For
more information, please visit www.lysa-lymphoma.org

Forward-Looking Statements

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statements can be identified by the words "expects," "anticipates,"
"believes," "intends," "estimates," "plans," "will," "outlook" and
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management's current plans, estimates, assumptions and projections, and
speak only as of the date they are made. We undertake 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 our Annual Report
on Form 10-K and our other reports filed with the Securities and
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