First New Front-Line Treatment Option for
HCC Approved in Japan in Nearly 10 Years
First Approval Under Global Strategic
Collaboration Between Eisai Co., Ltd. and Merck
Eisai Co., Ltd. and Merck (NYSE:MRK), known as MSD outside the
United States and Canada, today announced that the multiple
receptor tyrosine kinase inhibitor LENVIMA® (lenvatinib mesylate)
has been approved in Japan for unresectable hepatocellular
carcinoma (HCC). This is the first approval worldwide for LENVIMA
for the indication of unresectable HCC and the first new systemic
therapy to be approved in Japan for the front line treatment of HCC
in approximately 10 years. Additionally, this is the first
regulatory approval for LENVIMA under the global strategic
collaboration agreement executed in March 2018 between Eisai and
Merck for the co-development and co-commercialization of
LENVIMA.
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This approval was based on a phase 3 clinical study (Study
304/REFLECT study) conducted by Eisai investigating LENVIMA as a
first-line treatment in patients with unresectable HCC. In this
study, LENVIMA demonstrated statistically significant
non-inferiority of overall survival (OS) (13.6 months) compared to
sorafenib (12.3 months) (hazard ratio [HR] 0.92, 95% confidence
interval [CI]=0.79-1.06). Additionally, LENVIMA showed highly
statistically significant and clinically meaningful improvements as
compared to sorafenib in the secondary endpoints of
progression-free survival (PFS) (HR 0.66, 95% CI=0.57-0.77,
p<0.00001), time to progression (TTP) (HR 0.63, 95%
CI=0.53-0.73, p<0.00001), and objective response rate (ORR)
(LENVIMA 24% versus sorafenib 9%, p<0.00001). Furthermore,
LENVIMA helped to delay deterioration in several quality of life
(QOL) and symptom domains (pre-specified secondary endpoint),
including in areas such as pain and diarrhea, compared to sorafenib
(nominal p-value<0.05).
In this study, the five most common adverse events observed in
the LENVIMA arm were hypertension (42%), diarrhea (39%), decreased
appetite (34%), weight loss (31%) and fatigue (30%), which is
consistent with the known safety profile of LENVIMA.
Liver cancer is the second leading cause of cancer-related
deaths, with approximately 750,000 deaths per year estimated
globally. Additionally, approximately 780,000 cases are newly
diagnosed each year, about 80 percent of which occur in Asia,
including Japan and China. HCC accounts as the primary reason for
85 percent to 90 percent of liver cancer cases. It is estimated
that there are approximately 42,000 HCC patients in Japan, with
approximately 26,000 deaths every year. To date, treatment options
for unresectable HCC have been limited, and the prognosis is very
poor, emphasizing that this is an area of high unmet medical
need.
“With the approval of this additional indication of unresectable
HCC for LENVIMA, we are proud to be able to deliver the first new
front-line systemic therapy treatment option for HCC in Japan in
approximately 10 years, and expect this will contribute to HCC
treatment,” said Dr. Takashi Owa, Eisai Oncology Business Group
Chief Medicine Creation Officer. “Eisai will continue with its
efforts in oncology research and development in order to deliver
hopes for a potential cure for cancer to patients and their
families.”
“Today’s approval is an important first for LENVIMA and a
significant first regulatory event under our collaboration with
Eisai,” said Dr. Roy Baynes, Senior Vice President and Head of
Global Clinical Development, Chief Medical Officer, Merck Research
Laboratories. “We congratulate Eisai on the approval of this new
indication and look forward to working together to bring this
important treatment option to patients.”
Having received approval of this indication, Eisai will receive
a development milestone payment from Merck. There are no changes to
Eisai’s consolidated financial results forecasts for the fiscal
year ending March 31, 2018 based on the receipt of this milestone
payment.
LENVIMA Product Details in Japan (underlined parts have been
added)
1) Product name
LENVIMA® Capsule 4 mg
2) Generic name
Lenvatinib mesylate
3) Indication
Unresectable thyroid cancer, unresectable
hepatocellular carcinoma
4) Dosage and Administration
Unresectable thyroid cancer
The usual adult dose is 24 mg as lenvatinib administered orally
once a day. The dose may be reduced depending on the condition of
the individual patient.
Unresectable hepatocellular
carcinoma
The usual adult dose is an amount of
lenvatinib in accordance with body weight administered orally once
a day. For adults weighing 60 kg and over, the dose should be 12
mg. For adults weighing less than 60 kg, the dose should be 8 mg.
The dose may be reduced depending on the condition of the
individual patient.
About LENVIMA® (lenvatinib mesylate) capsules,
10 mg and 4 mg
Discovered by Eisai, LENVIMA is an orally administered multiple
receptor tyrosine kinase (RTK) inhibitor with a novel binding mode
that selectively inhibits the kinase activities of vascular
endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and
VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2,
FGFR3 and FGFR4) in addition to other pathway-related RTKs
(including the platelet-derived growth factor (PDGF) receptor
PDGFRα; KIT; and RET) involved in tumor angiogenesis, tumor
progression and modification of tumor immunity.
Currently, LENVIMA is approved as a treatment for refractory
thyroid cancer in over 50 countries, including the United States,
Japan, in Europe and Asia. Additionally, Eisai has obtained
approval for the agent in combination with everolimus as a
treatment for renal cell carcinoma (second-line) in over 40
countries, including the United States and in Europe. In Europe,
the agent was launched under the brand name Kisplyx® for renal cell
carcinoma.
Outside of Japan, Eisai has submitted applications for an
indication covering hepatocellular carcinoma in the United States
and Europe (July 2017), China (October 2017), Taiwan (December
2017) and other countries.
About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck 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 (endometrial cancer,
non-small cell lung cancer, hepatocellular carcinoma, head and neck
cancer, bladder cancer and melanoma), as well as a basket trial
targeting multiple cancer types.
About the REFLECT Study (Study 304)
The REFLECT study is a multicenter, open-label, randomized,
global phase 3 study comparing the efficacy and safety of LENVIMA
versus sorafenib, a standard treatment for advanced HCC, as a
first-line treatment for patients with unresectable HCC. In the
study, 954 patients were randomized in a 1:1 ratio to receive
LENVIMA 12 mg (≥60 kg) or 8 mg (<60 kg) once a day, depending on
baseline body weight (n=478), or sorafenib 400 mg twice a day
(n=476). Treatment was continued until disease progression or
unacceptable toxicity.
The primary endpoint of the study was OS, with the goal of
demonstrating non-inferiority. Other factors including PFS, TTP,
ORR and QOL were assessed as secondary endpoints. According to the
results of the study, LENVIMA met the statistical criteria for
non-inferiority in the primary endpoint of median OS (13.6 months)
compared to sorafenib (12.3 months) (HR 0.92, 95%
CI=0.79-1.06).
Additionally, LENVIMA showed statistically significant
improvements in the three secondary efficacy endpoints
(investigator assessment), doubling sorafenib's median values and
ratios: median PFS (LENVIMA 7.4 months versus sorafenib 3.7 months
[HR 0.66, 95% CI=0.57-0.77, p<0.00001]), median TTP (LENVIMA 8.9
months versus sorafenib 3.7 months [HR 0.63, 95% CI=0.53-0.73,
p<0.00001]) and ORR (LENVIMA 24% versus sorafenib 9%,
[p<0.00001]).
Furthermore, the European Organisation for Research and
Treatment of Cancer's (EORTC) health-related QOL questionnaires
QLQ-C30 and QLQ-HCC18 were used for the assessment. In both groups,
scores decreased after the administration of the agents. However,
within three categories in EORTC QLQ-C30 (role functioning, pain,
diarrhea) and two categories in QLQ-HCC18 (nutrition, body image),
it was found that LENVIMA helped to delay deterioration of QOL
compared to sorafenib (nominal p-value<0.05).
In this study, the five most common adverse events observed in
the LENVIMA arm were hypertension (42%), diarrhea (39%), decreased
appetite (34%), weight loss (31%) and fatigue (30%), which is
consistent with the known safety profile of LENVIMA.
LENVIMA® (lenvatinib) Indications in the
U.S.
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.
Important Safety Information
Warnings and Precautions
- In DTC, hypertension was reported in
73% of patients on LENVIMA (lenvatinib) 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,
including aortic dissection, 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 (lenvatinib)
+ everolimus vs 0% with everolimus alone. 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
- Impaired wound healing, including
fistula formation, has been reported in patients receiving LENVIMA.
Temporary interruption of LENVIMA therapy should be considered in
patients undergoing major surgical procedures
- 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 decrease (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 (lenvatinib) 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
For more information about LENVIMA, click here for the full
Prescribing Information.
About KEYTRUDA® (pembrolizumab) Injection
100mg
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.
KEYTRUDA® (pembrolizumab) Indications and
Dosing in the U.S.
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 (pembrolizumab), 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 (pembrolizumab) 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.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma who are not eligible
for cisplatin-containing chemotherapy. 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 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 (pembrolizumab) 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 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 (pembrolizumab) 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 (pembrolizumab) 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.
KEYTRUDA can cause other clinically important immune-mediated
adverse reactions. These immune-mediated reactions may occur in any
organ system. 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, and partial seizures arising in a patient with inflammatory
foci in brain parenchyma. In addition, myelitis and myocarditis
were reported in other clinical trials, including classical Hodgkin
lymphoma, 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 being treated with KEYTRUDA
(pembrolizumab). Of 23 patients with cHL who proceeded to
allogeneic HSCT after treatment with KEYTRUDA on any trial, 6
patients (26%) developed graft-versus-host disease (GVHD), one of
which was fatal, and 2 patients (9%) developed severe hepatic
veno-occlusive disease (VOD) after reduced-intensity conditioning,
one of which was fatal. 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.
These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT. Follow patients closely
for early evidence of transplant-related complications such as
hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
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 (pembrolizumab) 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-052, KEYTRUDA (pembrolizumab) 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.
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 KEYTRUDA for 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%).
Please see Prescribing Information for KEYTRUDA
(pembrolizumab) at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Patient Information/Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf
Eisai’s Focus on Cancer
Eisai regards oncology as a key therapeutic area and is aiming
to discover revolutionary new medicines with the potential to cure
cancer by leveraging drug creation base technologies cultivated
through the discovery of LENVIMA and Halaven, as well as
technologies associated with organic synthetic chemistry and drug
discovery science. Eisai’s research groups in Japan and the United
States are working on drug discovery activities using drug
discovery platforms mainly for the cancer microenvironment, driver
gene mutation and aberrant splicing in cancer cells, that are
Eisai’s strengths.
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 (hhc) philosophy.
With approximately 10,000 employees working across our global
network of R&D facilities, manufacturing sites and marketing
subsidiaries, we strive to realize our hhc 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.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
helping people fight cancer is our passion and supporting
accessibility to our cancer medicines is our commitment. Our focus
is on pursuing research in immuno-oncology and we are accelerating
every step in the journey – from lab to clinic – to potentially
bring new hope to people with cancer.
As part of our focus on cancer, Merck is committed to exploring
the potential of immuno-oncology with one of the fastest-growing
development programs in the industry. We are currently executing an
expansive research program evaluating our anti-PD-1 therapy across
more than 30 tumor types. We also continue to strengthen our
immuno-oncology portfolio through strategic acquisitions and are
prioritizing the development of several promising immunotherapeutic
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
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).
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Eisai Public Relations
Department+81-(0)3-3817-5120orEisai Investor
Relations+81-(0)3-3817-3016orMerck Media RelationsPamela
Eisele, 267-305-3558orAnn Bush, 908-740-6677orMerck Investor
RelationsTeri Loxam, 908-740-1986orPeter Dannenbaum,
908-740-1037
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