Market Overview

Eisai and Merck Announce FDA Grants Breakthrough Therapy Designation for LENVIMA® (lenvatinib) in Combination with KEYTRUDA® (pembrolizumab) as Therapy for Previously Treated Patients with Advanced and/or Metastatic non-MSI-H/pMMR Endometrial Carcinoma

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Eisai Co., Ltd. and Merck (NYSE:MRK), known as MSD outside the United
States and Canada, announced today that the U.S. Food and Drug
Administration (FDA) granted Breakthrough Therapy designation for LENVIMA®
(lenvatinib), the orally available kinase inhibitor discovered by Eisai,
in combination with Merck's anti-PD-1 therapy KEYTRUDA®
(pembrolizumab) for the potential treatment of patients with advanced
and/or metastatic non-microsatellite instability high (MSI-H)/proficient
mismatch repair (pMMR) endometrial carcinoma (EC) who have progressed
following at least one prior systemic therapy. The LENVIMA/KEYTRUDA
combination therapy is being jointly developed by Eisai and Merck as
part of the strategic collaboration announced in March 2018. This is the
third Breakthrough Therapy designation for LENVIMA and the second
Breakthrough Therapy designation for LENVIMA in combination with
KEYTRUDA, following the Breakthrough Therapy designation for the
combination for advanced and/or metastatic renal cell carcinoma
announced in January 2018.

The Breakthrough Therapy designation is an FDA program intended to
expedite development and review of medicines for serious or
life-threatening conditions. In order to qualify for this designation,
preliminary clinical evidence must demonstrate that the drug may provide
substantial improvement over currently available therapy on at least one
clinically significant endpoint. The benefits of this Breakthrough
Therapy designation include more intensive guidance on an efficient
clinical development program, access to senior FDA managers and
experienced FDA staff to help accelerate review time, as well as
eligibility for rolling review and potentially priority review.

This Breakthrough Therapy designation was based on interim results of
the EC cohort in Study 111/KEYNOTE-146, which were presented in June
2018 at the 54th American Society of Clinical Oncology (ASCO)
Annual Meeting. Study 111/KEYNOTE-146 is a multicenter, open-label,
single-arm Phase 1b/2 basket trial evaluating the efficacy and safety of
LENVIMA in combination with KEYTRUDA in patients with selected solid
tumors.

"This second Breakthrough Therapy designation for the LENVIMA/KEYTRUDA
combination represents another step forward in our collaboration with
Eisai and supports the continued evaluation of this combination in more
than 11 types of cancer," said Dr. Roy Baynes, senior vice president and
head of global clinical development, chief medical officer, Merck
Research Laboratories. "We will continue to work closely with Eisai to
build on the robust data for the LENVIMA/KEYTRUDA combination in
advanced endometrial carcinoma in an effort to offer a new option for
these patients and potentially help address a critical unmet need."

"We designed Study 111 to learn as much as we could about the
LENVIMA/KEYTRUDA combination as efficiently as possible, driven by a
sense of urgency to bring forward a potential new treatment option for
patients in need," said Dr. Takashi Owa, Vice President and Chief
Medicine Creation Officer, Oncology Business Group, Eisai. "We are
encouraged by the continued activity seen in patients with endometrial
carcinoma, and the latest Breakthrough Therapy designation for LENVIMA
and KEYTRUDA has strengthened our commitment, as part of our human
health care
mission, to expedite the path to ultimately benefitting
patients living with endometrial carcinoma as quickly as possible."

The combination of LENVIMA and KEYTRUDA is investigational. The efficacy
and safety of this combination has not been established. The
LENVIMA/KEYTRUDA combination is not approved in any cancer types today.

About Study 111/KEYNOTE-146

Study 111/KEYNOTE-146 is a multicenter, open-label, single-arm Phase
1b/2 basket trial evaluating the combination of LENVIMA (20 mg/day) with
KEYTRUDA (200 mg intravenously every three weeks) in patients with
selected solid tumors (renal cell carcinoma, EC, non-small cell lung
cancer, urothelial cancer, squamous cell head and neck cancer, and
melanoma). Patients were not preselected based on MSI or PD-L1 tumor
biomarker status. The primary endpoint of the Phase 1b study was to
determine the maximum tolerated dose of LENVIMA and KEYTRUDA in
combination. The primary endpoint of the Phase 2 portion is
investigator-assessed objective response rate (ORR) at week 24 based on
immune-related RECIST (irRECIST). The secondary efficacy endpoints
included ORR, progression-free survival and duration of response for
patients with complete or partial responses. Fifty-three patients with
previously treated, metastatic EC were evaluated in the EC cohort.
Currently, the Phase 2 part is ongoing, as an EC cohort expansion. This
study is being conducted under an existing strategic collaboration
between the two companies.

A randomized, international, two-arm Phase 3 study in recurrent EC is
underway (Study 309/KEYNOTE-775; NCT03517449; please visit clinicaltrials.gov
for more information).

About Endometrial Carcinoma

Endometrial cancer begins in the inner lining of the uterus
(endometrium), and nearly all cancers of the uterus are endometrial
carcinomas. In 2018, it is estimated there will be approximately 63,230
new cases of uterine cancer, and there will be approximately 11,350
deaths from uterine cancer (with the figures for endometrial cancer
being slightly lower than this combined estimate). Stages of endometrial
cancer range from stage 1 through 4. The five-year survival rate for
women diagnosed with stage 1A endometrial cancer is 88% and drops to 15%
for those diagnosed with stage 4B.

About the Eisai and Merck Strategic Collaboration

In March 2018, Eisai and Merck, through an affiliate, entered into a
strategic collaboration for the worldwide co-development and
co-commercialization of LENVIMA. Under the agreement, the companies will
develop and commercialize LENVIMA jointly, both as monotherapy and in
combination with Merck's anti-PD-1 therapy KEYTRUDA. In addition to
ongoing clinical studies of the combination, the companies will jointly
initiate new clinical studies evaluating the combination to support 11
potential indications in six types of cancer (bladder cancer,
endometrial cancer, head and neck cancer, hepatocellular carcinoma,
melanoma and non-small cell lung cancer), as well as a basket trial
targeting six additional cancer types. The combination is not approved
in any cancer types today.

About LENVIMA® (lenvatinib) capsules
4 mg and 10 mg

LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated
for:

  • Differentiated Thyroid Cancer (DTC): single agent for patients with
    locally recurrent or metastatic, progressive, radioactive
    iodine-refractory DTC.
  • Renal Cell Cancer (RCC): in combination with everolimus for patients
    with advanced RCC following one prior anti-angiogenic therapy.

LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that
inhibits the kinase activities of vascular endothelial growth factor
(VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA
inhibits other kinases that have been implicated in pathogenic
angiogenesis, tumor growth, and cancer progression in addition to their
normal cellular functions, including fibroblast growth factor (FGF)
receptors FGFR1-4; the platelet derived growth factor receptor alpha
(PDGFRα), KIT, and RET.

Important Safety Information

Warnings and Precautions

  • In DTC, hypertension was reported in 73% of patients on LENVIMA vs 16%
    with placebo (44% vs 4% grade ≥3). In RCC, hypertension was reported
    in 42% of patients on LENVIMA + everolimus vs 10% with everolimus
    alone (13% vs 2% grade 3). Serious complications of poorly controlled
    hypertension have been reported. Systolic blood pressure ≥160 mmHg
    occurred in 29% of patients, and 21% of patients had a diastolic blood
    pressure ≥100 mmHg in the LENVIMA + everolimus– treated group. Blood
    pressure should be controlled prior to treatment and monitored
    throughout. Withhold dose for grade 3 hypertension despite optimal
    antihypertensive therapy; resume at reduced dose when controlled at
    grade ≤2. Discontinue for life-threatening hypertension
  • In DTC, cardiac dysfunction was reported in 7% of patients on LENVIMA
    vs 2% with placebo (2% vs 0% grade ≥3). In RCC, decreased ejection
    fraction and cardiac failure were reported in 10% of patients on
    LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3).
    Monitor for signs/symptoms of cardiac decompensation. Withhold LENVIMA
    for development of grade 3 cardiac dysfunction until improvement to
    grade 0, 1, or baseline. Resume at reduced dose or discontinue based
    on severity and persistence of cardiac dysfunction. Discontinue for
    grade 4 cardiac dysfunction
  • In DTC, arterial thromboembolic events were reported in 5% of patients
    on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, arterial
    thromboembolic events were reported in 2% of patients on LENVIMA +
    everolimus vs 6% with everolimus alone (2% vs 4% grade ≥3).
    Discontinue following an arterial thrombotic event. The safety of
    resuming LENVIMA after an arterial thromboembolic event has not been
    established, and LENVIMA has not been studied in patients who have had
    an arterial thromboembolic event within the previous 6 months
  • Across clinical studies in which 1,160 patients received LENVIMA
    monotherapy, hepatic failure (including fatal events) was reported in
    3 patients and acute hepatitis in 1 patient. In DTC, ALT and AST
    increases (grade ≥3) occurred in 4% and 5% of patients on LENVIMA,
    respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade
    ≥3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0%
    with everolimus alone, respectively. Monitor liver function before
    initiation, then every 2 weeks for the first 2 months, and at least
    monthly thereafter during treatment. Withhold dose for liver
    impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume
    at reduced dose or discontinue based on severity/persistence of
    hepatotoxicity. Discontinue for hepatic failure
  • In DTC, proteinuria was reported in 34% of patients on LENVIMA vs 3%
    with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in
    31% of patients on LENVIMA + everolimus vs 14% with everolimus alone
    (8% vs 2% grade 3). Monitor for proteinuria before and during
    treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced
    dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
  • In RCC, diarrhea was reported in 81% of patients on LENVIMA +
    everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate
    prompt medical management for the development of diarrhea. Monitor for
    dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced
    dose when diarrhea resolves to grade 1 or baseline. Permanently
    discontinue LENVIMA for grade 4 diarrhea despite medical management
  • In DTC, events of renal impairment were reported in 14% of patients on
    LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, events of
    renal impairment were reported in 18% of patients on LENVIMA +
    everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold
    LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced
    dose or discontinue, depending on severity/persistence of renal
    impairment. Active management of diarrhea and any other
    gastrointestinal (GI) symptoms should be initiated for grade 1 events
  • In DTC, events of GI perforation or fistula were reported in 2% of
    patients on LENVIMA vs 0.8% with placebo. In RCC, events of GI
    perforation, abscess, or fistula (grade ≥3) were reported in 2% of
    patients on LENVIMA + everolimus vs 0% with everolimus alone. Fistulas
    and GI perforations have also been reported in other lenvatinib
    clinical trials and in postmarketing experience. Pneumothorax has been
    reported with and without clear evidence of a bronchopleural fistula.
    Some reports of GI perforation, fistula, and pneumothorax occurred in
    association with tumor regression or necrosis. In most cases of
    fistula formation or GI perforation, risk factors such as prior
    surgery or radiotherapy were present. Discontinue in patients who
    develop GI perforation or life-threatening fistula
  • In DTC, QT/QTc interval prolongation was reported in 9% of patients on
    LENVIMA vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval
    increases >60 ms were reported in 11% of patients on LENVIMA +
    everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor
    electrocardiograms in patients with congenital long QT syndrome,
    congestive heart failure, bradyarrhythmias, or patients taking drugs
    known to prolong the QT interval. Monitor and correct electrolyte
    abnormalities in all patients. Withhold dose for QTc interval
    prolongation >500 ms. Resume at reduced dose when QTc prolongation
    resolves to baseline
  • In DTC, hypocalcemia (grade ≥3) was reported in 9% of patients on
    LENVIMA vs 2% with placebo. In RCC, hypocalcemia (grade ≥3) was
    reported in 6% of patients on LENVIMA + everolimus vs 2% with
    everolimus alone. Monitor blood calcium levels at least monthly and
    replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
  • Across clinical studies in which 1,160 patients received LENVIMA
    monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS)
    was reported in 4 patients. Withhold LENVIMA for RPLS until fully
    resolved. Resume at reduced dose or discontinue based on the severity
    and persistence of neurologic symptoms
  • Across clinical studies in which 1,160 patients received LENVIMA
    monotherapy, hemorrhage (grade≥3) was reported in 2% of patients. In
    DTC, hemorrhagic events occurred in 35% of patients on LENVIMA vs 18%
    with placebo (2% vs 3% grade ≥3). There was 1 fatal intracranial
    hemorrhage case among 16 patients who received LENVIMA and had central
    nervous system metastases at baseline. The most frequently reported
    hemorrhagic event was epistaxis (11% grade 1, 1% grade 2).
    Discontinuation due to hemorrhagic events occurred in 1% of patients
    on LENVIMA. In RCC, hemorrhagic events occurred in 34% of patients on
    LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3).
    The most frequently reported hemorrhagic event was epistaxis (23% for
    LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal
    cerebral hemorrhage case. Discontinuation due to hemorrhagic events
    occurred in 3% of patients on LENVIMA + everolimus. Consider the risk
    of severe or fatal hemorrhage associated with tumor
    invasion/infiltration of major blood vessels (eg, carotid artery).
    Withhold LENVIMA for the development of grade 3 hemorrhage until
    resolved to grade 0 or 1. Resume at reduced dose or discontinue based
    on severity/persistence of hemorrhage. Discontinue for grade 4
    hemorrhage
  • In DTC patients with normal baseline thyroid-stimulating hormone
    (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline
    in 57% of patients on LENVIMA vs 14% with placebo. In RCC, grade 1 or
    2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus
    vs 2% with everolimus alone. In RCC patients with normal or low TSH at
    baseline, elevation of TSH was observed postbaseline in 60% of
    patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor
    thyroid function before initiation of and at least monthly throughout
    treatment. Treat hypothyroidism according to standard medical practice
    to maintain a euthyroid state
  • Wound healing complications, including fistula formation and wound
    dehiscence, can occur with LENVIMA. Withhold LENVIMA for at least 6
    days prior to scheduled surgery. Resume LENVIMA after surgery based on
    clinical judgment of adequate wound healing. Permanently discontinue
    LENVIMA in patients with wound healing complications
  • LENVIMA can cause fetal harm when administered to a pregnant woman.
    Advise females of reproductive potential to use effective
    contraception during treatment with LENVIMA and for at least 2 weeks
    following completion of therapy

Adverse Reactions

  • In DTC, the most common adverse reactions (≥30%) observed in
    LENVIMA-treated patients vs placebo-treated patients were hypertension
    (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%),
    arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%),
    weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs
    8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs
    3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal
    pain (31% vs 11%), and dysphonia (31% vs 5%)
  • In DTC, adverse reactions led to dose reductions in 68% of patients
    receiving LENVIMA and in 5% of patients receiving placebo; 18% of
    patients discontinued LENVIMA and 5% discontinued placebo for adverse
    reactions. The most common adverse reactions (≥10%) resulting in dose
    reductions of LENVIMA were hypertension (13%), proteinuria (11%),
    decreased appetite (10%), and diarrhea (10%); the most common adverse
    reactions (≥1%) resulting in discontinuation of LENVIMA were
    hypertension (1%) and asthenia (1%)
  • In RCC, the most common adverse reactions (>30%) observed in patients
    treated with LENVIMA + everolimus vs everolimus alone were diarrhea
    (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%),
    decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs
    16%), stomatitis/oral inflammation (44% vs 50%),
    hypertension/increased blood pressure (42% vs 10%), peripheral edema
    (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%),
    dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight
    decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and
    proteinuria/urine protein present (31% vs 14%). The most common
    serious adverse reactions (≥5%) were renal failure (11%), dehydration
    (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting
    (5%), and dyspnea (5%)
  • In RCC, adverse reactions led to dose reductions or interruption in
    89% of patients receiving LENVIMA + everolimus and in 54% of patients
    receiving everolimus alone. The most common adverse reactions (≥5%)
    resulting in dose reductions in the LENVIMA + everolimus–treated group
    were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting
    (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due
    to an adverse reaction occurred in 29% of patients in the LENVIMA +
    everolimus–treated group and in 12% of patients in the
    everolimus-treated group

Use in Specific Populations

  • Because of the potential for serious adverse reactions in nursing
    infants, advise women to discontinue breastfeeding during treatment
  • LENVIMA may result in reduced fertility in females of reproductive
    potential and may result in damage to male reproductive tissues,
    leading to reduced fertility of unknown duration

About KEYTRUDA® (pembrolizumab) Injection,
100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of
the body's immune system to help detect and fight tumor cells. KEYTRUDA
is a humanized monoclonal antibody that blocks the interaction between
PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes
which may affect both tumor cells and healthy cells.

Merck has the industry's largest immuno-oncology clinical research
program, which currently involves more than 750 trials studying KEYTRUDA
across a wide variety of cancers and treatment settings. The KEYTRUDA
clinical program seeks to understand the role of KEYTRUDA across cancers
and the factors that may predict a patient's likelihood of benefitting
from treatment with KEYTRUDA, including exploring several different
biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a fixed dose of 200 mg every three weeks until
disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment
of patients with metastatic non-small cell lung cancer (NSCLC) whose
tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as
determined by an FDA-approved test, with no EGFR or ALK genomic tumor
aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as
determined by an FDA-approved test, with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated
for the first-line treatment of patients with metastatic nonsquamous
NSCLC. This indication is approved under accelerated approval based on
tumor response rate and progression-free survival. Continued approval
for this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA
should be administered prior to chemotherapy when given on the same day.
See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC) with disease
progression on or after platinum-containing chemotherapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is
administered at a fixed dose of 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory classical Hodgkin lymphoma (cHL), or who have relapsed
after three or more prior lines of therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. In adults with cHL, KEYTRUDA is administered at a
fixed dose of 200 mg every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with cHL, KEYTRUDA is administered at
a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory primary mediastinal large B-cell lymphoma (PMBCL), or
who have relapsed after 2 or more prior lines of therapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in confirmatory trials. KEYTRUDA is not recommended for
the treatment of patients with PMBCL who require urgent cytoreductive
therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression. In pediatric
patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up
to a maximum of 200 mg) every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not eligible
for cisplatin-containing chemotherapy and whose tumors express PD-L1
[Combined Positive Score (CPS) ≥10], or in patients who are not eligible
for any platinum-containing chemotherapy regardless of PD-L1 status.
This indication is approved under accelerated approval based on tumor
response rate and duration of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is
administered at a fixed dose of 200 mg every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in patients
without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with unresectable or metastatic microsatellite instability-high (MSI-H)
or mismatch repair deficient (dMMR)

  • solid tumors that have progressed following prior treatment and who
    have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with
    fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The safety and
effectiveness of KEYTRUDA in pediatric patients with MSI-H central
nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed
dose of 200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression. In
children with MSI-H cancer, KEYTRUDA is administered at a dose of 2
mg/kg (up to a maximum of 200 mg) every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in patients
without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent
locally advanced or metastatic gastric or gastroesophageal junction
(GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score
(CPS) ≥1] as determined by an FDA-approved test, with disease
progression on or after two or more prior lines of therapy including
fluoropyrimidine- and platinum-containing chemotherapy and if
appropriate, HER2/neu-targeted therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of
200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic cervical cancer with disease progression on or after
chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an
FDA-approved test. This indication is approved under accelerated
approval based on tumor response rate and durability of response.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in the confirmatory
trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every
three weeks until disease progression, unacceptable toxicity or up to 24
months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.
Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA,
including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%)
pneumonitis, and occurred more frequently in patients with a history of
prior thoracic radiation (6.9%) compared to those without (2.9%).
Monitor patients for signs and symptoms of pneumonitis. Evaluate
suspected pneumonitis with radiographic imaging. Administer
corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA
for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or
recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48
(1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3
(1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms
of colitis. Administer corticosteroids for Grade 2 or greater colitis.
Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for
Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19
(0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver
function. Administer corticosteroids for Grade 2 or greater hepatitis
and, based on severity of liver enzyme elevations, withhold or
discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of
2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%),
and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of
hypophysitis (including hypopituitarism and adrenal insufficiency).
Administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for
Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%)
of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3
(0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799
patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%)
hypothyroidism.

The incidence of new or worsening hypothyroidism was higher in patients
with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including
Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799
patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis.
Monitor patients for changes in thyroid function (at the start of
treatment, periodically during treatment, and as indicated based on
clinical evaluation) and for clinical signs and symptoms of thyroid
disorders. Administer replacement hormones for hypothyroidism and manage
hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients.
Monitor patients for hyperglycemia or other signs and symptoms of
diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA
and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9
(0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal
function. Administer corticosteroids for Grade 2 or greater nephritis.
Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for
Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative
dermatitis, and bullous pemphigoid, can occur. Monitor patients for
suspected severe skin reactions and based on the severity of the adverse
reaction, withhold or permanently discontinue KEYTRUDA and administer
corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA
and refer the patient for specialized care for assessment and treatment.
If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue in patients receiving KEYTRUDA.
While immune-mediated adverse reactions usually occur during treatment
with PD-1/PD-L1 blocking antibodies, they may occur after
discontinuation of treatment. For suspected immune-mediated adverse
reactions, ensure adequate evaluation to confirm etiology or exclude
other causes. Based on the severity of the adverse reaction, withhold
KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or
less, initiate corticosteroid taper and continue to taper over at least
1 month. Based on limited data from clinical studies in patients whose
immune-related adverse reactions could not be controlled with
corticosteroid use, administration of other systemic immunosuppressants
can be considered. Resume KEYTRUDA when the adverse reaction remains at
Grade 1 or less following corticosteroid taper. Permanently discontinue
KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs
and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions
occurred in less than 1% (unless otherwise indicated) of 2799 patients:
arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia
gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and
encephalitis. In addition, myelitis and myocarditis were reported in
other clinical trials, including cHL, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use
of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection
in solid organ transplant recipients. Consider the benefit of treatment
with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have been
reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and
symptoms of infusion-related reactions, including rigors, chills,
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever.
For Grade 3 or 4 reactions, stop infusion and permanently discontinue
KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in
patients who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after treatment with KEYTRUDA. Of 23 patients
with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed
graft-versus-host disease (GVHD) (one fatal case), and 2 developed
severe hepatic veno-occlusive disease (VOD) after reduced-intensity
conditioning (one fatal case). Cases of fatal hyperacute GVHD after
allogeneic HSCT have also been reported in patients with lymphoma who
received a PD-1 receptor–blocking antibody before transplantation.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, Grade 3 to 4 acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.

In patients with a history of allogeneic HSCT, acute GVHD, including
fatal GVHD, has been reported after treatment with KEYTRUDA. Patients
who experienced GVHD after their transplant procedure may be at
increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA
vs the risk of GVHD in these patients.

In clinical trials in patients with multiple myeloma, the addition of
KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in
increased mortality. Treatment of these patients with a PD-1 or PD-L1
blocking antibody in this combination is not recommended outside of
controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. If used during pregnancy, or if the
patient becomes pregnant during treatment, apprise the patient of the
potential hazard to a fetus. Advise females of reproductive potential to
use highly effective contraception during treatment and for 4 months
after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9%
of 555 patients with advanced melanoma; adverse reactions leading to
discontinuation in more than one patient were colitis (1.4%), autoimmune
hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and
cardiac failure (0.4%). Adverse reactions leading to interruption of
KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea
(2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab
were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs
23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are
listed for ipilimumab only for those adverse reactions that occurred at
the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse
reactions in 8% of 682 patients with metastatic NSCLC. The most common
adverse event resulting in permanent discontinuation of KEYTRUDA was
pneumonitis (1.8%). Adverse reactions leading to interruption of
KEYTRUDA occurred in 23% of patients; the most common (≥1%) were
diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation
(1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common
adverse reactions (occurring in at least 20% of patients and at a higher
incidence than with docetaxel) were decreased appetite (25% vs 23%),
dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with
carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC,
KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse
reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney
injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA
occurred in 39% of patients; the most common (≥2%) were fatigue (8%),
neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and
pneumonitis (3.4%). The most common adverse reactions (≥20%) with
KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea
(68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting
(39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased
appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%),
dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%),
peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs
3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia
(15% vs 24%). This study was not designed to demonstrate a statistically
significant difference in adverse reaction rates for KEYTRUDA as
compared to carbo/pem alone for any specified adverse reaction.

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in
17% of 192 patients with HNSCC. Serious adverse reactions occurred in
45% of patients. The most frequent serious adverse reactions reported in
at least 2% of patients were pneumonia, dyspnea, confusional state,
vomiting, pleural effusion, and respiratory failure. The most common
adverse reactions (reported in at least 20% of patients) were fatigue,
decreased appetite, and dyspnea. Adverse reactions occurring in patients
with HNSCC were generally similar to those occurring in patients with
melanoma or NSCLC, with the exception of increased incidences of facial
edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening
hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5%
of 210 patients with cHL, and treatment was interrupted due to adverse
reactions in 26% of patients. Fifteen percent (15%) of patients had an
adverse reaction requiring systemic corticosteroid therapy. Serious
adverse reactions occurred in 16% of patients. The most frequent serious
adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia,
dyspnea, GVHD, and herpes zoster. Two patients died from causes other
than disease progression; one from GVHD after subsequent allogeneic HSCT
and one from septic shock. The most common adverse reactions (occurring
in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8%
of 53 patients with PMBCL, and treatment was interrupted due to adverse
reactions in 15%. Twenty-five percent (25%) of patients had an adverse
reaction requiring systemic corticosteroid therapy. Serious adverse
reactions occurred in 26% of patients and included: arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion
(2%), and pericarditis (2%). Six (11%) patients died within 30 days of
start of treatment. The most common adverse reactions (occurring in ≥20%
of patients) were musculoskeletal pain (30%), upper respiratory tract
infection and pyrexia (28% each), cough (26%), fatigue (23%), and
dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in
11% of 370 patients with locally advanced or metastatic urothelial
carcinoma. The most common adverse reactions (in ≥20% of patients) were
fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%),
constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients
(5%) died from causes other than disease progression. Five patients
(1.4%) who were treated with KEYTRUDA experienced sepsis which led to
death, and 3 patients (0.8%) experienced pneumonia which led to death.
Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of
patients; the most common (≥1%) were liver enzyme increase, diarrhea,
urinary tract infection, acute kidney injury, fatigue, joint pain, and
pneumonia. Serious adverse reactions occurred in 42% of patients, the
most frequent (≥2%) of which were urinary tract infection, hematuria,
acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8%
of 266 patients with locally advanced or metastatic urothelial
carcinoma. The most common adverse reaction resulting in permanent
discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions
leading to interruption of KEYTRUDA occurred in 20% of patients; the
most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%),
and colitis (1.1%). The most common adverse reactions (≥20%) in patients
who received KEYTRUDA vs those who received chemotherapy were fatigue
(38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%),
decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs
13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients, the most frequent (≥2%) of which were urinary tract infection,
pneumonia, anemia, and pneumonitis.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8%
of 98 patients (in Cohort E) with recurrent or metastatic cervical
cancer. Serious adverse reactions occurred in 39% of patients receiving
KEYTRUDA. The most frequent serious adverse reactions reported included
anemia (7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (occurring in
≥20% of patients) were fatigue (43%), musculoskeletal pain (27%),
diarrhea (23%), pain and abdominal pain (22% each), and decreased
appetite (21%).

It is not known whether KEYTRUDA is excreted in human milk. Because many
drugs are excreted in human milk, instruct women to discontinue nursing
during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study, 40
pediatric patients (16 children aged 2 years to younger than 12 years
and 24 adolescents aged 12 years to 18 years) with advanced melanoma,
lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid
tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients
received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34
patients (85%) receiving 2 doses or more. The safety profile in these
pediatric patients was similar to that seen in adults treated with
KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in
these patients when compared to adults under 65 years of age were
fatigue (45%), vomiting (38%), abdominal pain (28%),
hypertransaminasemia (28%), and hyponatremia (18%).

About Eisai Inc.

At Eisai Inc., human health care (hhc) is our goal. We
give our first thoughts to patients and their families, and helping to
increase the benefits health care provides. As the U.S. pharmaceutical
subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate
commitment to patient care that is the driving force behind our efforts
to discover and develop innovative therapies to help address unmet
medical needs.

Eisai is a fully integrated pharmaceutical business that operates in two
global business groups: oncology and neurology (dementia-related
diseases and neurodegenerative diseases). Each group functions as an
end-to-end global business with discovery, development, manufacturing
and marketing capabilities. Our U.S. headquarters, commercial and
clinical development organizations are located in New Jersey; our
discovery labs are in Massachusetts and Pennsylvania; and our global
demand chain organization resides in Maryland and North Carolina. To
learn more about Eisai Inc., please visit us at eisai.com/us.

Merck's Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck, the potential
to bring new hope to people with cancer drives our purpose and
supporting accessibility to our cancer medicines is our commitment.

As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the largest development
programs in the industry across more than 30 tumor types. We also
continue to strengthen our portfolio through strategic acquisitions and
are prioritizing the development of several promising oncology
candidates with the potential to improve the treatment of advanced
cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For more than a century, Merck, a leading global biopharmaceutical
company known as MSD outside of the United States and Canada, has been
inventing for life, bringing forward medicines and vaccines for many of
the world's most challenging diseases. Through our prescription
medicines, vaccines, biologic therapies and animal health products, we
work with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to health care through far-reaching policies, programs
and partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world - including cancer,
cardio-metabolic diseases, emerging animal diseases, Alzheimer's disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com
and connect with us on Twitter,
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and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the
"company") includes "forward-looking statements" within the meaning of
the safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. These statements are based upon the current beliefs
and expectations of the company's management and are subject to
significant risks and uncertainties. There can be no guarantees with
respect to pipeline products that the products will receive the
necessary regulatory approvals or that they will prove to be
commercially successful. If underlying assumptions prove inaccurate or
risks or uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation in the
United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; the company's ability to
accurately predict future market conditions; manufacturing difficulties
or delays; financial instability of international economies and
sovereign risk; dependence on the effectiveness of the company's patents
and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause results
to differ materially from those described in the forward-looking
statements can be found in the company's 2017 Annual Report on Form 10-K
and the company's other filings with the Securities and Exchange
Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Please see Prescribing Information for LENVIMA (lenvatinib) at http://www.lenvima.com/pdfs/prescribing-information.pdf

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and
Medication Guide for KEYTRUDA at 
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.

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