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Eisai and Merck Announce European Commission Grants Marketing Authorization for LENVIMA® (lenvatinib) as First-Line Treatment in Adults with Advanced or Unresectable Hepatocellular Carcinoma

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First new, first-line treatment option for advanced or unresectable
HCC approved in Europe in a decade

Eisai and Merck (NYSE:MRK), known as MSD outside the United States and
Canada, announced today that the European Commission (EC) has granted a
marketing authorization for the oral receptor tyrosine kinase (RTK)
inhibitor LENVIMA® (lenvatinib), as a single agent for the
first-line treatment of adult patients with advanced or unresectable
hepatocellular carcinoma (HCC) who have received no prior systemic
therapy. Treatment options for this type of liver cancer are limited,
and the prognosis is poor. LENVIMA is the first new,
first-line treatment for advanced or unresectable HCC in a decade to
show an overall survival (OS) treatment effect by statistical
confirmation of non-inferiority against standard of care.

This press release features multimedia. View the full release here:
https://www.businesswire.com/news/home/20180823005176/en/

Liver cancer is the second leading cause of cancer-related deaths and is
estimated to be responsible for nearly 750,000 deaths per year globally
(69,000 per year in Europe), with over 780,000 cases newly diagnosed
each year (71,000 per year in Europe). Hepatocellular carcinoma
represents about 90 percent of primary liver cancer cases and due to the
underlying nature of the disease, surgery is generally not an option.

"Patients with hepatocellular carcinoma are faced with a cancer that is
difficult to treat and has a particularly poor prognosis, with only one
systemic first-line treatment option currently available," said Gary
Hendler, Chairman and CEO, Eisai EMEA. "LENVIMA is the first new
treatment option to be made available in this first-line systemic
treatment setting in over a decade and represents an important new
therapeutic option for patients. Eisai and Merck are therefore committed
to working together to ensure that patients have rapid access to LENVIMA
across Europe."

"Today's approval brings an important new first-line treatment option to
patients with hepatocellular carcinoma in Europe," said Dr. Jonathan
Cheng, vice president, oncology clinical research, Merck Research
Laboratories. "As a result of our efforts with Eisai on LENVIMA, we
continue to make significant progress in gaining regulatory approval in
countries around the world, as we strive together to make this medicine
available to patients in need as quickly as possible."

This approval was based on results from REFLECT (Study 304), an
open-label, Phase 3 trial where LENVIMA demonstrated a treatment effect
on OS by statistical confirmation of non-inferiority when compared with
the standard of care, sorafenib, in 954 patients with previously
untreated unresectable HCC. LENVIMA also demonstrated statistically
significant superiority and clinically meaningful improvements in
progression-free survival (PFS) and objective response rate (ORR).

Currently, LENVIMA is marketed in Japan for the treatment of HCC and in
the United States for the treatment of first-line unresectable HCC, and
applications seeking approval for this indication have been submitted to
additional countries.

About the REFLECT Trial (Study 304)
REFLECT was a large
(n=954), Phase 3, randomized, multi-center, open-label trial conducted
by Eisai to compare the efficacy and safety of LENVIMA versus sorafenib
as a first-line systemic treatment in patients with unresectable HCC.
Patients at 154 trial sites in 20 countries were randomized to receive
LENVIMA 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60
kg, respectively) (n=478) or sorafenib 400 mg twice a day (n=476).
Treatment was continued until disease progression or unacceptable
toxicity. The primary endpoint of this study was OS, tested first for
non-inferiority to sorafenib, then for superiority. The key secondary
efficacy endpoints of this study included PFS, time to progression (TTP)
and ORR, tested for superiority to sorafenib.

REFLECT showed that LENVIMA achieved the primary endpoint, demonstrating
a treatment effect on OS by statistical confirmation of non-inferiority
to sorafenib. Patients treated with LENVIMA experienced a median OS of
13.6 months compared to 12.3 months with sorafenib (HR: 0.92; 95% CI:
0.79–1.06). The OS analysis was conducted as prespecified in the
statistical analysis plan when 351 events had occurred in the LENVIMA
arm and 350 events had occurred in the sorafenib arm. Patients
randomized to the LENVIMA arm did not have a statistically significant
improvement in OS compared to those in the sorafenib arm. LENVIMA showed
statistically significant superiority and clinically meaningful
improvements in the secondary efficacy endpoints of PFS and ORR, as
confirmed by a blinded independent imaging review (IIR):

  • Median PFS was doubled with LENVIMA compared to sorafenib: 7.3 months
    versus 3.6 months (HR: 0.64; 95% CI: 0.55–0.75; p<0.0001) per blinded
    independent imaging review based on mRECIST criteria, and 7.3 months
    with LENVIMA versus 3.6 months with sorafenib (HR: 0.65; 95% CI:
    0.56–0.77; p<0.0001) per RECIST 1.1.
  • LENVIMA showed nearly 3.5 times the ORR of sorafenib: 41% (95% CI:
    36-45%) vs. 12% (95% CI: 9-15%) per blinded independent imaging review
    based on mRECIST criteria, respectively (p<0.0001), and 19% (95% CI:
    15-22%) with LENVIMA versus 7% (95% CI: 4-9%) with sorafenib per
    RECIST 1.1.
  • In REFLECT, the most common adverse events (all grades) observed in
    ≥30% of patients treated with LENVIMA were hypertension, diarrhea,
    decreased appetite, fatigue and decreased weight. Fatal adverse events
    determined by the investigator to be related to LENVIMA treatment
    occurred in 11 (2%) patients and included hepatic failure (three
    patients), cerebral hemorrhage (three patients), and respiratory
    failure (two patients).

The results of the REFLECT trial were published online in The Lancet
(Vol 391(10126):1163-1173)
on February 9, 2018.

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
(PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative
activity in hepatocellular carcinoma cell lines dependent on activated
FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α
(FRS2α) phosphorylation.

Important Safety Information in the U.S.

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.

For more information about LENVIMA please see available full Prescribing
Information
.

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® (pembrolizumab). In
addition to ongoing clinical studies of the combination, the companies
will jointly initiate new clinical studies evaluating the
LENVIMA/KEYTRUDA combination to support 11 potential indications in six
types of cancer, as well as a basket trial targeting six additional
cancer types. The LENVIMA/KEYTRUDA combination is not approved in any
cancer types today.

About Eisai Co., Ltd.
Eisai Co., Ltd. is a leading global
research and development-based pharmaceutical company headquartered in
Japan. We define our corporate mission as "giving first thought to
patients and their families and to increasing the benefits health care
provides," which we call our human health care philosophy.
With over 10,000 employees working across our global network of R&D
facilities, manufacturing sites and marketing subsidiaries, we strive to
realize our human health care philosophy by delivering
innovative products in various therapeutic areas with high unmet medical
needs, including Oncology and Neurology.

As a global pharmaceutical company, our mission extends to patients
around the world through our investment and participation in
partnership-based initiatives to improve access to medicines in
developing and emerging countries.

For more information about Eisai Co., Ltd., please visit www.eisai.com.

The development of lenvatinib underscores Eisai's human health care
mission, the company's commitment to innovative solutions in disease
prevention, cure and care for the health and well-being of people
worldwide. Eisai is committed to the therapeutic area of oncology and to
address the unmet medical needs of patients and their families.

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,
Facebook,
Instagram,
YouTube
and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA
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news release of Merck & Co., Inc., Kenilworth, N.J., USA (the "company")
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