TOKYO and KENILWORTH, N.J., Jan.
9, 2018 /PRNewswire/ -- Eisai Co., Ltd. and Merck
(NYSE:MRK), known as MSD outside the
United States and Canada,
announced today that they received Breakthrough Therapy Designation
from the U.S. Food and Drug Administration (FDA) for Eisai's
multiple receptor tyrosine kinase inhibitor LENVIMA®
(lenvatinib) in combination with Merck's anti-PD-1 therapy
KEYTRUDA® (pembrolizumab) for the potential treatment of
patients with advanced and/or metastatic renal cell carcinoma
(RCC). The LENVIMA and KEYTRUDA combination therapy is being
jointly developed by Eisai and Merck. This is the second
Breakthrough Therapy Designation for LENVIMA and the twelfth
Breakthrough Therapy Designation granted to KEYTRUDA.
The Breakthrough Therapy Designation is an FDA program intended
to expedite development and review of drugs for serious or
life-threatening conditions. In order to qualify for this
designation, preliminary clinical evidence must demonstrate that
the drug may provide substantial improvement over currently
available therapy on at least one clinically significant endpoint.
The benefits of this Breakthrough Therapy Designation include more
intensive guidance on an efficient drug development program, access
to a regulatory liaison to help accelerate review time and
eligibility for rolling review as well as priority review.
This Breakthrough Therapy Designation was based on the results
of the RCC cohort in Study 111, a multicenter, open-label phase
1b/2 clinical study being carried out
in the U.S. and the European Union (EU) to evaluate the efficacy
and safety of LENVIMA in combination with KEYTRUDA in subjects with
selected solid tumors.
Dr. Takashi Owa, Vice President,
Chief Medicine Creation Officer, Oncology Business Group, Eisai,
commented: "We are encouraged that the FDA has recognized the
potential of LENVIMA plus KEYTRUDA for patients with advanced
and/or metastatic renal cell carcinoma with the Breakthrough
Therapy Designation. As a human health care company
dedicated to giving our first thought to patients, we are committed
to working closely with Merck and the FDA to expedite this clinical
program with the hope that we may offer another important option
for patients in need."
"The FDA's Breakthrough Therapy Designation for the LENVIMA and
KEYTRUDA combination in advanced and/or metastatic renal cell
carcinoma provides us with the opportunity to accelerate our effort
to bring an important potential treatment option to these
patients," said Dr. Roy Baynes,
senior vice president and head of global clinical development,
chief medical officer, Merck Research Laboratories. "We remain
committed to understanding the full potential of KEYTRUDA across
cancers and treatment settings, and our collaboration with Eisai is
one of the many ways we are executing on this commitment to helping
more patients."
The combination of LENVIMA (lenvatinib) and KEYTRUDA
(pembrolizumab) is investigational. The efficacy and safety of this
combination has not been established.
About Study 111
Study 111 is a multicenter, open-label phase 1b/2 clinical study being carried out in the U.S.
and EU to evaluate the efficacy and safety of LENVIMA in
combination with KEYTRUDA. The primary objective of the phase
1b part was to determine the maximum
tolerated dose. Patients with unresectable solid tumors (renal cell
carcinoma, endometrial cancer, non-small cell lung cancer,
urothelial cancer, squamous cell head and neck cancer and melanoma)
who had progressed after treatment with approved therapies or for
which there are no standard effective therapies available were
administered 24 mg of LENVIMA orally daily, as well as 200 mg of
KEYTRUDA intravenously every three weeks. Dose reductions of
LENVIMA were permitted based on observed toxicity. The phase 2 part
was conducted with patients who had select solid tumors with 0-2
prior lines of systemic therapy (unless discussed with the
sponsor), with a recommended dosage of 20 mg of LENVIMA daily and
200 mg of KEYTRUDA every three weeks as determined based on the
results of the phase 1b part. The
primary endpoint of the phase 2 part was objective response rate at
24 weeks after treatment began, with select secondary endpoints
including objective response rate, disease control rate,
progression-free survival and duration of response. Currently, the
phase 2 part is underway, with enrollment expanded for the
endometrial cancer cohort.
About Renal Cell Carcinoma
In 2012, the number of
patients with renal cancer was estimated to be approximately
338,000 worldwide, including approximately 58,000 in the US,
115,000 in Europe and 17,000 in
Japan. In the US, approximately
63,990 new cases were estimated to occur in 2017. Approximately
25–30 percent of patients are estimated to present with metastatic
disease at time of diagnosis. Renal cell carcinoma comprises
approximately 90 percent of all malignancies of the kidney, and
originates from malignant cells in the lining of the tubules of the
kidney. The average age of a renal cancer diagnosis is 64, and it
is more likely to affect men than women. For advanced or metastatic
renal cell carcinoma that is difficult to treat with surgery, the
standard treatment is molecular targeted drug therapy. However,
this remains a disease with significant unmet medical need.
About LENVIMA® (lenvatinib)
LENVIMA® (lenvatinib) is a kinase inhibitor that is
indicated for:
- Differentiated Thyroid Cancer (DTC): single agent for patients
with locally recurrent or metastatic, progressive, radioactive
iodine-refractory DTC.
- Renal Cell Cancer (RCC): in combination with everolimus for
patients with advanced RCC following one prior anti-angiogenic
therapy.
LENVIMA, discovered and developed by Eisai, is a receptor
tyrosine kinase (RTK) inhibitor that inhibits the kinase activities
of vascular endothelial growth factor (VEGF) receptors VEGFR1
(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA also inhibits
other RTKs 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. The combination of LENVIMA 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.
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, 100 mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the
ability of the body's immune system to help detect and fight tumor
cells. KEYTRUDA is a humanized monoclonal antibody that blocks the
interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby
activating T lymphocytes which may affect both tumor cells and
healthy cells.
Merck has the industry's largest immuno-oncology clinical
research program, which currently involves more than 650 trials
studying KEYTRUDA across a wide variety of cancers and treatment
settings. The KEYTRUDA clinical program seeks to understand the
role of KEYTRUDA across cancers and the factors that may predict a
patient's likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
KEYTRUDA (pembrolizumab) Indications and Dosing 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 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
(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.
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 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® (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving
KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%),
and 5 (0.1%) pneumonitis, and occurred more frequently in patients
with a history of prior thoracic radiation (6.9%) compared to those
without (2.9%). Monitor patients for signs and symptoms of
pneumonitis. Evaluate suspected pneumonitis with radiographic
imaging. Administer corticosteroids for Grade 2 or greater
pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue
KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
KEYTRUDA can cause immune-mediated colitis. Colitis
occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA,
including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%)
colitis.Monitor patients for signs and symptoms of colitis.
Administer corticosteroids for Grade 2 or greater colitis. Withhold
KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for
Grade 4 colitis.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for
changes in liver function. Administer corticosteroids for Grade 2
or greater hepatitis and, based on severity of liver enzyme
elevations, withhold or discontinue KEYTRUDA (pembrolizumab).
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17
(0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients
for signs and symptoms of hypophysitis (including hypopituitarism
and adrenal insufficiency). Administer corticosteroids and hormone
replacement as clinically indicated. Withhold KEYTRUDA for Grade 2;
withhold or discontinue for Grade 3 or 4 hypophysitis.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96
(3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237
(8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2
(6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or
worsening hypothyroidism was higher in patients with HNSCC,
occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3
(0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799
patients receiving KEYTRUDA, including Grade 2(0.3%) thyroiditis.
Monitor patients for changes in thyroid function (at the start of
treatment, periodically during treatment, and as indicated based on
clinical evaluation) and for clinical signs and symptoms of thyroid
disorders. Administer replacement hormones for hypothyroidism and
manage hyperthyroidism with thionamides and beta-blockers as
appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4
hyperthyroidism.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799
patients. Monitor patients for hyperglycemia or other signs and
symptoms of diabetes. Administer insulin for type 1 diabetes, and
withhold KEYTRUDA and administer antihyperglycemics in patients
with severe hyperglycemia.
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for
changes in renal function. Administer corticosteroids for Grade 2
or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Immune-mediated rashes, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN) (some cases with fatal
outcome), exfoliative dermatitis, and bullous pemphigoid, can
occur. Monitor patients for suspected severe skin reactions and
based on the severity of the adverse reaction, withhold or
permanently discontinue KEYTRUDA and administer corticosteroids.
For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer
the patient for specialized care for assessment and treatment. If
SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
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 (pembrolizumab). 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. 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.
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. The most common adverse reactions
(in 20% of patients) were fatigue (38%), musculoskeletal pain
(24%), decreased appetite (22%), constipation (21%), rash (21%),
and diarrhea (20%). Eighteen patients (5%) died from causes other
than disease progression. Five patients (1.4%) who were treated
with KEYTRUDA experienced sepsis which led to death, and 3 patients
(0.8%) experienced pneumonia which led to death. Adverse reactions
leading to interruption of KEYTRUDA occurred in 22% of patients;
the most common (≥1%) were liver enzyme increase, diarrhea, urinary
tract infection, acute kidney injury, fatigue, joint pain, and
pneumonia. Serious adverse reactions occurred in 42% of patients,
the most frequent (≥2%) of which were urinary tract infection,
hematuria, acute kidney injury, pneumonia, and urosepsis.
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or metastatic
urothelial carcinoma. The most common adverse reaction resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Adverse reactions leading to interruption of KEYTRUDA occurred in
20% of patients; the most common (≥1%) were urinary tract infection
(1.5%), diarrhea (1.5%), and colitis (1.1%). The most common
adverse reactions (≥20%) in patients who received KEYTRUDA vs those
who received chemotherapy were fatigue (38% vs 56%),
musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased
appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients, the most frequent (≥2%) of which were urinary tract
infection, pneumonia, anemia, and pneumonitis.
It is not known whether KEYTRUDA (pembrolizumab) 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.
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 over 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
Merck's 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 2016
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).
Contacts:
|
|
|
|
Eisai Public
Relations Department
|
Merck Media
Relations
|
+81-(0)3-3817-5120
|
Pamela Eisele: (267)
305-3558
|
Laurie Landau: (201)
746-2510
|
Ann Bush: (908)
740-6677
|
Michele Randazzo:
(201) 746-2979
|
|
|
|
Eisai Investor
Relations
|
Merck Investor
Relations
|
+81-(0)3-3817-5327
|
Teri Loxam: (908)
740-1986
|
Ivor Macleod: (201)
746-2660
|
Michael DeCarbo:
(908) 740-1807
|
View original
content:http://www.prnewswire.com/news-releases/eisai-and-merck-receive-breakthrough-therapy-designation-from-fda-for-lenvima-lenvatinib-mesylate-and-keytruda-pembrolizumab-as-combination-therapy-for-advanced-andor-metastatic-renal-cell-carcinoma-300579517.html
SOURCE Eisai Inc.