New Data from Investigational Study of LENVIMA® (lenvatinib) and
KEYTRUDA® (pembrolizumab) Combination in Three Different Tumor Types Presented at the Society for
Immunotherapy of Cancer’s 33rd Annual Meeting
First presentation of LENVIMA and KEYTRUDA combination data in patients with metastatic non-small cell lung
cancer, metastatic melanoma and metastatic urothelial carcinoma from Study 111/KEYNOTE-146
New data support ongoing broad clinical program for LENVIMA and KEYTRUDA combination across multiple tumor
types
Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Merck (NYSE:MRK), known as MSD outside the United States
and Canada, today announced results from presentations of new data and analyses of LENVIMA® (lenvatinib), an orally
available kinase inhibitor discovered by Eisai, in combination with Merck’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab)
in three different tumor types – metastatic non-small cell lung cancer (NSCLC) (Abstract #11147), metastatic melanoma (Abstract
#11187) and metastatic urothelial carcinoma (Abstract #11201).
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These data from the Study 111/KEYNOTE-146 Phase 1b/2 trial will be presented at the 33rd Annual Meeting of the
Society for Immunotherapy of Cancer (SITC) in Washington, D.C. from November 9-11. In the interim analyses of the studies across
three tumor types, the LENVIMA and KEYTRUDA combination demonstrated encouraging anti-tumor activity. These data support further
evaluation of the combination. LENVIMA and KEYTRUDA are not approved for use in combination in any cancer types today.
“We are increasingly confident that these interim analyses of new clinical trial data on the combination of LENVIMA and KEYTRUDA
in non-small cell lung cancer, melanoma and urothelial cancer continue to verify the potential of this combination,” said Dr.
Takashi Owa, Vice President and Chief Medicine Creation Officer, Oncology Business Group at Eisai. “Through our collaboration with
Merck, we are doing our utmost to be able to provide this combination to patients in need of new treatment options as soon as
possible.”
“These early promising data being presented support the clinical strategy behind our study of KEYTRUDA in combination with
LENVIMA across a range of different cancers,” said Dr. Jonathan Cheng, Vice President, Oncology Clinical Research, Merck Research
Laboratories. “We look forward to continuing our broad clinical research effort in collaboration with Eisai to evaluate these two
therapies in combination, with the goal of improving treatment outcomes for people living with cancer.”
Trial Design and New Data for Study 111/KEYNOTE-146
Study 111/KEYNOTE-146 is a multi-center, open-label, single-arm, Phase 1b/2 basket trial (ClinicalTrials.gov, NCT02501096)
evaluating the combination of LENVIMA (20 mg/day) with KEYTRUDA (200 mg intravenously every three weeks) in patients with selected
solid tumors (metastatic endometrial cancer, metastatic head and neck cancer, metastatic melanoma, metastatic NSCLC, metastatic
renal cell carcinoma and metastatic urothelial carcinoma). Patients were not preselected based on PD-L1 tumor expression 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 (PFS) and duration of response (DOR)
for patients with complete or partial responses. Data from Study 111/KEYNOTE-146 are being presented at SITC’s 33rd
Annual Meeting from the metastatic NSCLC, metastatic melanoma and metastatic urothelial carcinoma cohorts.
Phase 1b/2 trial of lenvatinib in combination with pembrolizumab in patients with NSCLC (Abstract #11147/Poster
#P392)
As of data cutoff on March 1, 2018, 21 patients with metastatic NSCLC who either had no prior therapy or had received up to two
prior lines of therapy were enrolled in this Phase 2 cohort. The primary endpoint of ORR at week 24 per irRECIST was 33.3% (95% CI:
14.6-57.0). For secondary endpoints, median PFS per irRECIST was 5.9 months (95% CI: 2.3-13.8), and the PFS rate at 12 months per
irRECIST was 29.0% (95% CI: 10.2-51.0). Median DOR was 10.9 months (95% CI: 2.4-not estimable). Grade 3 treatment-related adverse
events (TRAEs) occurred in 10 patients (48%), and Grade 4 TRAEs occurred in one patient (5%). The most common TRAEs (any grade)
?30% were decreased appetite (67%), fatigue (62%), hypothyroidism (43%), diarrhea (43%), proteinuria (43%), arthralgia (33%) and
hypertension (33%). There was one treatment-related death.
Phase 1b/2 trial of lenvatinib in combination with pembrolizumab in patients with advanced melanoma (Abstract
#11187/Poster #P391)
As of March 1, 2018, 21 patients with metastatic melanoma who either had no prior therapy or had received up to two prior lines
of therapy were enrolled in this cohort. The primary endpoint of ORR at week 24 per irRECIST was 47.6% (95% CI: 25.7-70.2). For
secondary endpoints, median PFS was 5.5 months (95% CI: 2.6-15.8), and the PFS rate at 12 months was 34.7% (95% CI: 14.5-56.0). In
addition, median DOR was 12.5 months (95% CI: 2.7-not estimable). All patients experienced at least one TRAE. Grade 3 or 4 TRAEs
occurred in 14 patients (67%). The most common TRAEs (any grade) ?30% were fatigue (52%), decreased appetite (48%), diarrhea (48%),
hypertension (48%), dysphonia (43%), nausea (43%), arthralgia (33%) and proteinuria (33%). There were no treatment-related
deaths.
Phase 1b/2 trial of lenvatinib in combination with pembrolizumab in patients with urothelial cancer (Abstract
#11201/Poster #P393)
As of March 1, 2018, 20 patients with metastatic urothelial cancer who either had no prior therapy or had received up to two
prior lines of therapy were enrolled in this cohort. The primary endpoint of ORR at week 24 per irRECIST was 25% (95% CI: 9-49).
For secondary endpoints, median PFS was 5.4 months (95% CI: 1.3-not estimable). Eighteen patients (90%) experienced TRAEs. Grade 3
or 4 TRAEs occurred in 10 patients (50%). The most common TRAEs (any grade) ?30% were proteinuria (45%), diarrhea (40%),
hypertension (35%), fatigue (30%) and hypothyroidism (30%). There was one treatment-related death.
About LENVIMA® (lenvatinib) capsules 10 mg and 4 mg
LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated in the U.S.:
- For the treatment of patients with locally recurrent or metastatic, progressive radioactive
iodine-refractory differentiated thyroid cancer (DTC)
- In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma
(RCC) following one prior anti-angiogenic therapy
- For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
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 (PDGFR?), KIT, and
RET. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by
decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse
xenograft models of human renal cell cancer greater than each drug alone. Lenvatinib also exhibited antiproliferative activity in
hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2?
(FRS2?) phosphorylation.
Important Safety Information
Warnings and Precautions
Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred
in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ?160 mmHg occurred in 29% of patients, and 21%
had diastolic blood pressure ?100 mmHg. In HCC, hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4
hypertension was not reported in HCC.
Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor
blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment.
Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.
Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients
with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical
symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on
severity.
Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events
of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to
3% across all clinical trials.
Permanently discontinue following an arterial thrombotic event. The safety of resuming 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.
Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC,
serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and
hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5%
grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to
hepatic encephalopathy and 1% discontinued due to hepatic failure.
Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during
treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at
reduced dose upon recovery or permanently discontinue based on severity.
Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment
was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred
in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal
failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).
Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or
permanently discontinue for renal failure or impairment based on severity.
Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3
proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA
+ everolimus (8% grade 3).
Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ?2+ is detected,
obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea
occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose
interruption/reduction, and diarrhea recurred despite dose reduction.
Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on
severity.
Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in
DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Fistulas and gastrointestinal perforations have also
been reported in other lenvatinib clinical trials and in post-marketing experience. Pneumothorax has been reported with and without
clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula, and pneumothorax occurred in
association with tumor regression or necrosis. In most cases of fistula formation or gastrointestinal perforation, risk factors
such as prior surgery or radiotherapy were present.
Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.
QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval
prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving
LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of
LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.
Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in
patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to
prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on
severity.
Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia
improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4
hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of
LENVIMA-treated patients.
Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced
dose upon recovery or permanently discontinue depending on severity.
Reversible Posterior Leukoencephalopathy Syndrome. Across clinical studies of 1,823 patients who received LENVIMA as a
single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or
permanently discontinue depending on severity and persistence of neurologic symptoms.
Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical
trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in
combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients)
were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal
intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage
occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage
occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events.
Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in
the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in
patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have
not been demonstrated in clinical trials.
Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg,
carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression.
In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ?0.5 mU/L. In patients with normal TSH at baseline,
elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2
hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In
patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC
and 60% of LENVIMA + everolimus–treated patients in RCC.
Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard
medical practice.
Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur
with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate
wound healing. Permanently discontinue in patients with wound healing complications.
Embryo-fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause
fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during
organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats
and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective
contraception during treatment with LENVIMA and for at least 30 days after the last dose.
Adverse Reactions
In DTC, the most common adverse reactions (?30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%),
diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%),
headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and
dysphonia (31%). The most common serious adverse reactions (?2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse
reactions (?10%) resulting in dose reductions 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 LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue
(73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%),
peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events
(32%), and proteinuria (31%). The most common serious adverse reactions (?5%) were renal failure (11%), dehydration (10%), anemia
(6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or
interruption in 89% of patients. The most common adverse reactions (?5%) resulting in dose reductions 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 HCC, the most common adverse reactions (?20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%),
diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar
erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea
(20%). The most common serious adverse reactions (?2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and
decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse
reactions (?5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%),
hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction
occurred in 20% of patients. The most common adverse reactions (?1%) resulting in discontinuation of LENVIMA were fatigue (1%),
hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).
Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during
treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.
No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment.
LENVIMA concentrations may increase in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose
for patients with RCC or DTC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal
impairment. LENVIMA has not been studied in patients with end stage renal disease.
No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose
for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
No dose adjustment is recommended for patients with DTC or RCC and mild or moderate hepatic impairment. LENVIMA concentrations
may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe
hepatic impairment.
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. There are currently more than 850 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 benefiting 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, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with
metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of
patients with metastatic squamous NSCLC.
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 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.
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 the chemotherapy agents administered in combination with KEYTRUDA, as
appropriate.
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 3 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] as determined by
an FDA-approved test, 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 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
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients
receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), 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.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%). 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.
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). 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.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of
patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including
Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 15%
(28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and
thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic
ketoacidosis, occurred in 0.2% (6/2799) of patients.
Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function
(prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone
replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis.
Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA
and administer antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including
Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in
combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids
for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
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.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving
KEYTRUDA and may also 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 and
postmarketing use.
Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these patients.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4
reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with
KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1
fatal case) and 2 developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 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 graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic
veno-occlusive disease (VOD), and other immune-mediated adverse reactions.
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.
Increased Mortality in Patients With Multiple Myeloma
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.
Embryofetal Toxicity
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.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent 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%). The most common adverse reactions (?20%) with KEYTRUDA were
fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC,
KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (?20%) with
KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting
(24%), cough (21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or nab-paclitaxel in metastatic squamous
NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in
KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and
peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm
in KEYNOTE-407.
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%). The most common adverse
reactions (?20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
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 (?20%) 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 and new or worsening
hypothyroidism.
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ?1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients
died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most
common adverse reactions (?20%) 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. 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 (?20%)
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. Serious adverse reactions occurred in 42% of patients; those ?2% were urinary tract infection, hematuria,
acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (?20%) were fatigue (38%), musculoskeletal pain
(24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
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%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ?2% were urinary tract infection, pneumonia, anemia,
and pneumonitis. The most common adverse reactions (?20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal
pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or
NSCLC.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical
cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula,
hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (?20%) were fatigue
(43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
Lactation
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.
Pediatric Use
There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or
PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile 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 the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a
strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies
will jointly develop and commercialize LENVIMA, 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
LENVIMA and KEYTRUDA 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 LENVIMA and KEYTRUDA combination is not approved in any cancer types today.
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
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Instagram,
YouTube 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 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.
Eisai Co., Ltd. Media Relations
+81-(0)3-3817-5120
or
Eisai Inc. Media Relations
Michele Randazzo, 201-746-2979
or
Eisai Investor Relations
+81-(0)3-3817-3016
or
Merck Media Relations
Pamela Eisele, 267-305-3558
or
Kristen Drake, 908-334-4688
or
Merck Investor Relations
Teri Loxam, 908-740-1986
or
Michael DeCarbo, 908-740-1807
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