Results From New Analysis Evaluating
Health-Related Quality of Life (HRQoL) Based on Patient-Reported
Outcomes Using Three HRQoL Scales
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, and Eisai Inc. today announced new investigational data
from the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial, which
evaluated the combinations of KEYTRUDA, Merck’s anti-PD-1 therapy,
plus LENVIMA, the orally available multiple receptor tyrosine
kinase inhibitor discovered by Eisai, and LENVIMA plus everolimus
versus sunitinib for the first-line treatment of patients with
advanced renal cell carcinoma (RCC). Results from a new analysis
evaluating health-related quality of life (HRQoL) based on
patient-reported outcomes are being presented during an oral
abstract session at the 2021 American Society of Clinical Oncology
(ASCO) Annual Meeting (Abstract #4502). Data from
CLEAR/KEYTNOTE-581 were originally presented at the 2021
Genitourinary Cancers Symposium (ASCO GU) and published in the New
England Journal of Medicine, and data from this trial are currently
under review with the U.S. Food and Drug Administration (FDA).
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“This new analysis expands our understanding of the results
we’ve seen from the CLEAR/KEYNOTE-581 trial in the treatment of
patients with advanced renal cell carcinoma,” said Dr. Robert
Motzer, Medical Oncologist, Kidney Cancer Section Head,
Genitourinary Oncology Service, Memorial Sloan Kettering Cancer
Center. “The additional data showed an improvement of specific
health-related quality of life measures for patients who received
KEYTRUDA plus LENVIMA compared with sunitinib, supporting the
importance of this combination as a potential new first-line
treatment option for patients.”
“We continue to see an increasing number of patients diagnosed
with advanced renal cell carcinoma and remain committed to
improving outcomes for those facing this difficult-to-treat
disease,” said Dr. Gregory Lubiniecki, Vice President, Oncology
Clinical Research, Merck Research Laboratories. “This new analysis
builds on earlier findings from the CLEAR/KEYNOTE-581 trial and
further supports the potential use of KEYTRUDA plus LENVIMA for the
treatment of patients in the first-line setting.”
“This analysis addresses questions of interest to healthcare
professionals who treat patients with advanced renal cell carcinoma
and reinforces the KEYTRUDA plus LENVIMA combination as a possible
new treatment option for patients with this disease,” said Dr.
Takashi Owa, Chief Medicine Creation Officer and Chief Discovery
Officer, Oncology Business Group at Eisai. “These results reflect
Eisai and Merck’s shared commitment to relentlessly pursue thorough
scientific investigations with the goal of improving cancer
care.”
Data From Health‐Related Quality of Life (HRQoL) Analysis
From CLEAR/KEYNOTE-581
In an analysis of a secondary endpoint of HRQoL scores in the
CLEAR/KEYNOTE-581 trial, KEYTRUDA plus LENVIMA and LENVIMA plus
everolimus were evaluated to determine the impact on HRQoL compared
to sunitinib in patients with advanced RCC. This was assessed based
on patient-reported outcomes using three HRQoL and symptom
measures: Functional Assessment of Cancer Therapy Kidney Symptom
Index – Disease-Related Symptoms (FKSI-DRS), European Organisation
for Research and Treatment of Cancer Quality of Life Questionnaire
for Patients With Cancer – Core 30 (EORTC QLQ-C30) and European
Quality of Life Five-Dimensions – 3-Level System (EuroQoL
EQ-5D-3L). Unless otherwise noted, HRQoL analyses were based on
data from randomized patients who received at least one dose of
study treatment. No adjustments for multiple testing or estimation
were used; p-values (two-sided) and confidence intervals (CI) are
nominal and descriptive. Longitudinal change from baseline was
assessed by mixed model analysis. Least squares mean differences
(LSMD) and 95% CI were calculated from baseline. Time to
deterioration (based on changes in HRQoL and disease-related
symptom scores ≥ meaningful thresholds) was assessed using time to
first deterioration (TTD), which is the number of weeks between
randomization and the first deterioration event, and time until
definitive deterioration (TUDD), which is the number of weeks
between randomization and the earliest deterioration event with no
subsequent recovery above the deterioration threshold or no
subsequent HRQoL assessment data. All times to deterioration were
calculated and compared using the Kaplan-Meier method, stratified
log-rank tests and Cox models.
KEYTRUDA plus LENVIMA demonstrated similar changes from baseline
at mean follow-up (Week 46) on 14 out of 18 HRQoL and
disease-related symptom scores and better HRQoL and disease-related
symptom scores for the following measures (LSMD [95% CI]): physical
functioning (3.01 [0.48, 5.54]), fatigue (-2.80 [-5.52, -0.08]),
dyspnea (-2.79 [-5.33, -0.25]) and constipation (-2.19 [-4.19,
-0.18]), as measured by the QLQ-C30, versus sunitinib. LENVIMA plus
everolimus demonstrated similar changes from baseline at mean
follow-up (Week 46) on 14 out of 18 HRQoL and disease-related
symptom scores and worse HRQoL and disease-related symptom scores
in the following measures (LSMD [95% CI]): Global Health Score/QoL
(-2.81 [-5.08, -0.54]), pain (2.80 [0.11, 5.49]), appetite loss
(4.23 [1.34, 7.13]) and diarrhea (5.26 [2.61, 7.91]) compared to
sunitinib.
KEYTRUDA plus LENVIMA demonstrated a similar TTD in 14 out of 18
HRQoL and disease-related symptom scores, and a delay in TTD for
physical functioning, dyspnea, appetite loss, and EQ-5D visual
analog scale compared to sunitinib. KEYTRUDA plus LENVIMA
demonstrated a delay in TUDD in 16 out of 18 HRQoL and
disease-related symptom scores and a similar TUDD for cognitive
functioning and financial difficulties compared to sunitinib.
Dr. Motzer has provided consulting and advisory services for
Merck and Eisai.
About CLEAR (Study 307)/KEYNOTE-581
The CLEAR/KEYNOTE-581 trial is a multicenter, randomized,
open-label, Phase 3 trial (ClinicalTrials.gov, NCT02811861)
evaluating LENVIMA in combination with KEYTRUDA or in combination
with everolimus versus sunitinib for the first-line treatment of
patients with advanced RCC. The primary endpoint is
progression-free survival, as assessed by independent review per
RECIST v1.1. Secondary endpoints include overall survival,
objective response rate, HRQoL and safety. A total of 1,069
patients were randomized (1:1:1) to receive:
- LENVIMA (20 mg orally once daily) in combination with KEYTRUDA
(200 mg intravenously [IV] every three weeks for up to 24 months);
or
- LENVIMA (18 mg orally once daily) in combination with
everolimus (5 mg orally once daily); or
- Sunitinib (50 mg orally once daily for four weeks on treatment,
followed by two weeks off treatment).
Treatment continued until unacceptable toxicity or disease
progression as determined by the investigator and confirmed by
independent radiologic review committee using RECIST v1.1.
Administration of KEYTRUDA plus LENVIMA was permitted beyond
RECIST-defined disease progression if the patient was clinically
stable and considered by the investigator to be deriving clinical
benefit. KEYTRUDA was continued for a maximum of 24 months;
however, treatment with LENVIMA could be continued beyond 24
months. Assessment of tumor status was performed at baseline and
then every eight weeks.
About Renal Cell Carcinoma (RCC)
Worldwide, it is estimated there were more than 431,000 new
cases of kidney cancer diagnosed and more than 179,000 deaths from
the disease in 2020. In the U.S., it is estimated there will be
nearly 76,000 new cases of kidney cancer diagnosed and almost
14,000 deaths from the disease in 2021. Renal cell carcinoma is by
far the most common type of kidney cancer; about nine out of 10
kidney cancer diagnoses are RCC. Renal cell carcinoma is about
twice as common in men as in women. Most cases of RCC are
discovered incidentally during imaging tests for other abdominal
diseases. Approximately 30% of patients with RCC will have
metastatic disease at diagnosis, and as many as 40% will develop
metastases after primary surgical treatment for localized RCC.
Survival is highly dependent on the stage at diagnosis, and the
five-year survival rate is 13% for patients with metastatic
disease.
About KEYTRUDA® (pembrolizumab) Injection, 100 mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA is a humanized monoclonal antibody that blocks the
interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby
activating T lymphocytes which may affect both tumor cells and
healthy cells.
Merck has the industry’s largest immuno-oncology clinical
research program. There are currently more than 1,400 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.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph node(s) following complete
resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of patients
with metastatic nonsquamous non-small cell lung cancer (NSCLC),
with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with NSCLC expressing PD-L1 [tumor proportion
score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is stage III where
patients are not candidates for surgical resection or definitive
chemoradiation, or metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%)
as determined by an FDA-approved test, with disease progression on
or after platinum-containing chemotherapy. Patients with EGFR or
ALK genomic tumor aberrations should have disease progression on
FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic
or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with metastatic or with unresectable,
recurrent HNSCC whose tumors express PD-L1 [combined positive score
(CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic HNSCC with disease
progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with
relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients
with refractory cHL, or cHL that has relapsed after 2 or more lines
of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with refractory primary mediastinal large B-cell lymphoma
(PMBCL), or who have relapsed after 2 or more prior lines of
therapy. KEYTRUDA is not recommended for treatment of patients with
PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not
eligible for cisplatin-containing chemotherapy and whose tumors
express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or
in patients who are not eligible for any platinum-containing
chemotherapy regardless of PD-L1 status. This indication is
approved under accelerated approval based on tumor response rate
and duration of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who have disease
progression during or following platinum-containing chemotherapy or
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with
Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle
invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with
or without papillary tumors who are ineligible for or have elected
not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient
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.
Microsatellite Instability-High or Mismatch Repair Deficient
Colorectal Cancer
KEYTRUDA is indicated for the first-line treatment of patients
with unresectable or metastatic MSI-H or dMMR colorectal cancer
(CRC).
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, and fluoropyrimidine-
and platinum-containing chemotherapy, is indicated for the
first-line treatment of patients with locally advanced unresectable
or metastatic HER2-positive gastric or gastroesophageal junction
(GEJ) adenocarcinoma. 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.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma whose tumors express
PD-L1 (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.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic esophageal or gastroesophageal junction
(GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ)
carcinoma that is not amenable to surgical resection or definitive
chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based
chemotherapy, or
- as a single agent after one or more prior lines of systemic
therapy for patients with tumors of squamous cell histology that
express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cervical cancer with disease progression on
or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as
determined by an FDA-approved test. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. 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.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma (MCC). 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.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the
first-line treatment of patients with advanced renal cell carcinoma
(RCC).
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the
treatment of patients with advanced endometrial carcinoma that is
not MSI-H or dMMR, who have disease progression following prior
systemic therapy and are not candidates for curative surgery or
radiation. 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 trial.
Tumor Mutational Burden-High
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic tumor mutational
burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as
determined by an FDA-approved test, that have progressed following
prior treatment and who have no satisfactory alternative treatment
options. 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
TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cutaneous squamous cell carcinoma (cSCC)
that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA, in combination with chemotherapy, is indicated for the
treatment of patients with locally recurrent unresectable or
metastatic triple-negative breast cancer (TNBC) whose tumors
express PD-L1 (CPS ≥10) as determined by an FDA-approved test. This
indication is approved under accelerated approval based on
progression-free survival. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of
drugs that bind to either the programmed death receptor-1 (PD-1) or
the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1
pathway, thereby removing inhibition of the immune response,
potentially breaking peripheral tolerance and inducing
immune-mediated adverse reactions. Immune-mediated adverse
reactions, which may be severe or fatal, can occur in any organ
system or tissue, can affect more than one body system
simultaneously, and can occur at any time after starting treatment
or after discontinuation of treatment. Important immune-mediated
adverse reactions listed here may not include all possible severe
and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be
clinical manifestations of underlying immune-mediated adverse
reactions. Early identification and management are essential to
ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and
periodically during treatment. In cases of suspected
immune-mediated adverse reactions, initiate appropriate workup to
exclude alternative etiologies, including infection. Institute
medical management promptly, including specialty consultation as
appropriate.
Withhold or permanently discontinue KEYTRUDA depending on
severity of the immune-mediated adverse reaction. In general, if
KEYTRUDA requires interruption or discontinuation, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement
to Grade 1 or less, initiate corticosteroid taper and continue to
taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose adverse reactions are
not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is
higher in patients who have received prior thoracic radiation.
Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients
receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3
(0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were
required in 67% (63/94) of patients. Pneumonitis led to permanent
discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9%
(26) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 23% had recurrence.
Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL
receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3%
of patients. Patients received high-dose corticosteroids for a
median duration of 10 days (range: 2 days to 53 months).
Pneumonitis rates were similar in patients with and without prior
thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA
in 5.4% (21) of patients. Of the patients who developed
pneumonitis, 42% of these patients interrupted KEYTRUDA, 68%
discontinued KEYTRUDA, and 77% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present
with diarrhea. Cytomegalovirus infection/reactivation has been
reported in patients with corticosteroid-refractory immune-mediated
colitis. In cases of corticosteroid-refractory colitis, consider
repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 1.7% (48/2799) of patients
receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%),
and Grade 2 (0.4%) reactions. Systemic corticosteroids were
required in 69% (33/48); additional immunosuppressant therapy was
required in 4.2% of patients. Colitis led to permanent
discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5%
(13) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 23% had recurrence.
Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated
Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated
hepatitis occurred in 0.7% (19/2799) of patients receiving
KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 68%
(13/19) of patients; additional immunosuppressant therapy was
required in 11% of patients. Hepatitis led to permanent
discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9)
of patients. All patients who were withheld reinitiated KEYTRUDA
after symptom improvement; of these, none had recurrence. Hepatitis
resolved in 79% of the 19 patients.
KEYTRUDA with Axitinib
KEYTRUDA in combination with axitinib can cause hepatic
toxicity. Monitor liver enzymes before initiation of and
periodically throughout treatment. Consider monitoring more
frequently as compared to when the drugs are administered as single
agents. For elevated liver enzymes, interrupt KEYTRUDA and
axitinib, and consider administering corticosteroids as needed.
With the combination of KEYTRUDA and axitinib, Grades 3 and 4
increased alanine aminotransferase (ALT) (20%) and increased
aspartate aminotransferase (AST) (13%) were seen, which was at a
higher frequency compared to KEYTRUDA alone. Fifty-nine percent of
the patients with increased ALT received systemic corticosteroids.
In patients with ALT ≥3 times upper limit of normal (ULN) (Grades
2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92
patients who were rechallenged with either KEYTRUDA (n=3) or
axitinib (n=34) administered as a single agent or with both (n=55),
recurrence of ALT ≥3 times ULN was observed in 1 patient receiving
KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving
both. All patients with a recurrence of ALT ≥3 ULN subsequently
recovered from the event.
Immune-Mediated
Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency.
For Grade 2 or higher, initiate symptomatic treatment, including
hormone replacement as clinically indicated. Withhold KEYTRUDA
depending on severity. Adrenal insufficiency occurred in 0.8%
(22/2799) of patients receiving KEYTRUDA, including Grade 4
(<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic
corticosteroids were required in 77% (17/22) of patients; of these,
the majority remained on systemic corticosteroids. Adrenal
insufficiency led to permanent discontinuation of KEYTRUDA in
<0.1% (1) and withholding in 0.3% (8) of patients. All patients
who were withheld reinitiated KEYTRUDA after symptom
improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis
can present with acute symptoms associated with mass effect such as
headache, photophobia, or visual field defects. Hypophysitis can
cause hypopituitarism. Initiate hormone replacement as indicated.
Withhold or permanently discontinue KEYTRUDA depending on severity.
Hypophysitis occurred in 0.6% (17/2799) of patients receiving
KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2
(0.2%) reactions. Systemic corticosteroids were required in 94%
(16/17) of patients; of these, the majority remained on systemic
corticosteroids. Hypophysitis led to permanent discontinuation of
KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All
patients who were withheld reinitiated KEYTRUDA after symptom
improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders.
Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism. Initiate hormone
replacement for hypothyroidism or institute medical management of
hyperthyroidism as clinically indicated. Withhold or permanently
discontinue KEYTRUDA depending on severity. Thyroiditis occurred in
0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2
(0.3%). None discontinued, but KEYTRUDA was withheld in <0.1%
(1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving
KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to
permanent discontinuation of KEYTRUDA in <0.1% (2) and
withholding in 0.3% (7) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement. Hypothyroidism
occurred in 8% (237/2799) of patients receiving KEYTRUDA, including
Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent
discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5%
(14) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement. The majority of patients with
hypothyroidism required long-term thyroid hormone replacement. The
incidence of new or worsening hypothyroidism was higher in 1185
patients with HNSCC, occurring in 16% of patients receiving
KEYTRUDA as a single agent or in combination with platinum and FU,
including Grade 3 (0.3%) hypothyroidism. The incidence of new or
worsening hypothyroidism was higher in 389 adult patients with cHL
(17%) receiving KEYTRUDA as a single agent, including Grade 1
(6.2%) and Grade 2 (10.8%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic
Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms
of diabetes. Initiate treatment with insulin as clinically
indicated. Withhold KEYTRUDA depending on severity. Type 1 DM
occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to
permanent discontinuation in <0.1% (1) and withholding of
KEYTRUDA in <0.1% (1). All patients who were withheld
reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal
Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated
nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA,
including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%)
reactions. Systemic corticosteroids were required in 89% (8/9) of
patients. Nephritis led to permanent discontinuation of KEYTRUDA in
0.1% (3) and withholding in 0.1% (3) of patients. All patients who
were withheld reinitiated KEYTRUDA after symptom improvement; of
these, none had recurrence. Nephritis resolved in 56% of the 9
patients.
Immune-Mediated Dermatologic Adverse
Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis.
Exfoliative dermatitis, including Stevens-Johnson syndrome, drug
rash with eosinophilia and systemic symptoms, and toxic epidermal
necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical
emollients and/or topical corticosteroids may be adequate to treat
mild to moderate nonexfoliative rashes. Withhold or permanently
discontinue KEYTRUDA depending on severity. Immune-mediated
dermatologic adverse reactions occurred in 1.4% (38/2799) of
patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 40%
(15/38) of patients. These reactions led to permanent
discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6%
(16) of patients. All patients who were withheld reinitiated
KEYTRUDA after symptom improvement; of these, 6% had recurrence.
The reactions resolved in 79% of the 38 patients.
Other Immune-Mediated Adverse
Reactions
The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received KEYTRUDA or were reported with the
use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have
been reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous
System: Meningitis, encephalitis, myelitis and demyelination,
myasthenic syndrome/myasthenia gravis (including exacerbation),
Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy;
Ocular: Uveitis, iritis and other ocular inflammatory toxicities
can occur. Some cases can be associated with retinal detachment.
Various grades of visual impairment, including blindness, can
occur. If uveitis occurs in combination with other immune-mediated
adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome,
as this may require treatment with systemic steroids to reduce the
risk of permanent vision loss; Gastrointestinal: Pancreatitis, to
include increases in serum amylase and lipase levels, gastritis,
duodenitis; Musculoskeletal and Connective Tissue:
Myositis/polymyositis rhabdomyolysis (and associated sequelae,
including renal failure), arthritis (1.5%), polymyalgia rheumatica;
Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic
anemia, aplastic anemia, hemophagocytic lymphohistiocytosis,
systemic inflammatory response syndrome, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune
thrombocytopenic purpura, solid organ transplant rejection.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor
for signs and symptoms of infusion-related reactions. Interrupt or
slow the rate of infusion for Grade 1 or Grade 2 reactions. For
Grade 3 or Grade 4 reactions, stop infusion and permanently
discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Fatal and other serious complications can occur in patients who
receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatment.
Transplant-related complications include hyperacute
graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic
veno-occlusive disease after reduced intensity conditioning, and
steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between anti–PD-1/PD-L1 treatment and
allogeneic HSCT. Follow patients closely for evidence of these
complications and intervene promptly. Consider the benefit vs risks
of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic
HSCT.
Increased Mortality in Patients With Multiple Myeloma
In 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 an
anti–PD-1/PD-L1 treatment in this combination is not recommended
outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm
when administered to a pregnant woman. Advise women of this
potential risk. In females of reproductive potential, verify
pregnancy status prior to initiating KEYTRUDA and advise them to
use effective contraception during treatment and for 4 months after
the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent discontinuation in more than one
patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic
reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%).
The most common adverse reactions (≥20%) with KEYTRUDA were fatigue
(28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-054, KEYTRUDA was permanently discontinued due to
adverse reactions in 14% of 509 patients; the most common (≥1%)
were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious
adverse reactions occurred in 25% of patients receiving KEYTRUDA.
The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea
(28%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions
in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia,
pneumonia, and urinary tract infection. Adverse reactions observed
in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with
the exception that increased incidences of alopecia (47% vs 36%)
and peripheral neuropathy (31% vs 25%) were observed in the
KEYTRUDA and chemotherapy arm compared to the placebo and
chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients with advanced NSCLC; the most
common were pneumonitis (3%), death due to unknown cause (1.6%),
and pneumonia (1.4%). The most frequent serious adverse reactions
reported in at least 2% of patients were pneumonia (7%),
pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion
(2.2%). The most common adverse reaction (≥20%) was fatigue
(25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common was pneumonitis (1.8%). The most common adverse
reactions (≥20%) were decreased appetite (25%), fatigue (25%),
dyspnea (23%), and nausea (20%).
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to
adverse events in 12% of 300 patients with HNSCC; the most common
adverse reactions leading to permanent discontinuation were sepsis
(1.7%) and pneumonia (1.3%). The most common adverse reactions
(≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination
with platinum (cisplatin or carboplatin) and FU chemotherapy,
KEYTRUDA was discontinued due to adverse reactions in 16% of 276
patients with HNSCC. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%),
pneumonitis (1.8%), and septic shock (1.4%). The most common
adverse reactions (≥20%) were nausea (51%), fatigue (49%),
constipation (37%), vomiting (32%), mucosal inflammation (31%),
diarrhea (29%), decreased appetite (29%), stomatitis (26%), and
cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse
reactions in 17% of 192 patients with HNSCC. Serious adverse
reactions occurred in 45% of patients. The most frequent serious
adverse reactions reported in at least 2% of patients were
pneumonia, dyspnea, confusional state, vomiting, pleural effusion,
and respiratory failure. The most common adverse reactions (≥20%)
were fatigue, decreased appetite, and dyspnea. Adverse reactions
occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy, with the exception of increased incidences of
facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse
reactions in 14% of 148 patients with cHL. Serious adverse
reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1%
were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney
injury, febrile neutropenia, and sepsis. Three patients died from
causes other than disease progression: 2 from complications after
allogeneic HSCT and 1 from unknown cause. The most common adverse
reactions (≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue,
rash, and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis,
pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from
causes other than disease progression: 1 from GVHD after subsequent
allogeneic HSCT and 1 from septic shock. The most common adverse
reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. Serious adverse reactions occurred
in 42% of patients; those ≥2% were urinary tract infection,
hematuria, acute kidney injury, pneumonia, and urosepsis. The most
common adverse reactions (≥20%) were fatigue (38%), musculoskeletal
pain (24%), decreased appetite (22%), constipation (21%), rash
(21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or metastatic
urothelial carcinoma. The most common adverse reaction resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients; those ≥2% were urinary tract infection, pneumonia,
anemia, and pneumonitis. The most common adverse reactions (≥20%)
in patients who received KEYTRUDA were fatigue (38%),
musculoskeletal pain (32%), pruritus (23%), decreased appetite
(21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse
reactions in 11% of 148 patients with high-risk NMIBC. The most
common adverse reaction resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred
in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia
(2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and
urinary tract infection (2%). The most common adverse reactions
(≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC
were similar to those occurring in patients with melanoma or NSCLC
who received KEYTRUDA as a monotherapy.
In KEYNOTE-811, when KEYTRUDA was administered in combination
with trastuzumab, fluoropyrimidine- and platinum-containing
chemotherapy, KEYTRUDA was discontinued due to adverse reactions in
6% of 217 patients with locally advanced unresectable or metastatic
HER2-positive gastric or gastroesophageal junction (GEJ)
adenocarcinoma. The most common adverse reaction resulting in
permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA
arm versus placebo, there was a difference of ≥5% incidence between
patients treated with KEYTRUDA versus standard of care for diarrhea
(53% vs 44%) and nausea (49% vs 44%).
The most common adverse reactions (≥20%) in patients receiving
KEYTRUDA in combination with chemotherapy were fatigue/asthenia,
nausea, constipation, diarrhea, decreased appetite, rash, vomiting,
cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal
inflammation, stomatitis, headache, and weight loss.
Adverse reactions occurring in patients with gastric cancer who
received KEYTRUDA as a monotherapy were similar to those occurring
in patients with melanoma or NSCLC who received KEYTRUDA as a
monotherapy.
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin
and fluorouracil to patients with metastatic or locally advanced
esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above
the GEJ) carcinoma who were not candidates for surgical resection
or definitive chemoradiation, KEYTRUDA was discontinued due to
adverse reactions in 15% of 370 patients. The most common adverse
reactions resulting in permanent discontinuation of KEYTRUDA (≥1%)
were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia
(1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in
combination with chemotherapy were nausea (67%), fatigue (57%),
decreased appetite (44%), constipation (40%), diarrhea (36%),
vomiting (34%), stomatitis (27%), and weight loss (24%).
Adverse reactions occurring in patients with esophageal cancer
who received KEYTRUDA as a monotherapy were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA
as a monotherapy.
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with recurrent or metastatic
cervical cancer. Serious adverse reactions occurred in 39% of
patients receiving KEYTRUDA; the most frequent included anemia
(7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (≥20%)
were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%),
pain and abdominal pain (22% each), and decreased appetite
(21%).
Adverse reactions occurring in patients with hepatocellular
carcinoma (HCC) were generally similar to those in patients with
melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the
exception of increased incidences of ascites (8% Grades 3-4) and
immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades
3-4) that occurred at a higher incidence were elevated AST (20%),
ALT (9%), and hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination
with axitinib, fatal adverse reactions occurred in 3.3% of 429
patients. Serious adverse reactions occurred in 40% of patients,
the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%),
acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%); the most common were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and
cerebrovascular accident (1.2%). The most common adverse reactions
(≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension
(48%), hepatotoxicity (39%), hypothyroidism (35%), decreased
appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea
(28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash
(25%), cough (21%), and constipation (21%).
In KEYNOTE-146, when KEYTRUDA was administered in combination
with LENVIMA to patients with endometrial carcinoma (n=94), fatal
adverse reactions occurred in 3% of patients. Serious adverse
reactions occurred in 52% of patients, the most common (≥3%) were
hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%),
hemorrhage, fatigue, nausea, confusional state, and pleural
effusion (4% each), adrenal insufficiency, colitis, dyspnea, and
pyrexia (3% each). KEYTRUDA was discontinued for adverse reactions
(Grade 1-4) in 19% of patients, regardless of action taken with
LENVIMA; the most common (≥2%) leading to discontinuation of
KEYTRUDA were adrenal insufficiency, colitis, pancreatitis, and
muscular weakness (2% each). The most common adverse reactions
(≥20%) observed with KEYTRUDA in combination with LENVIMA were
fatigue, musculoskeletal pain and hypertension (65% each), diarrhea
(64%), decreased appetite (52%), hypothyroidism (51%), nausea
(48%), stomatitis (43%), vomiting (39%), weight loss (36%),
abdominal pain and headache (33% each), constipation (32%), urinary
tract infection (31%), dysphonia (29%), hemorrhagic events (28%),
hypomagnesemia(27%), palmar-plantar erythrodysesthesia syndrome
(26%), dyspnea (24%), and cough and rash (21% each).
Adverse reactions occurring in patients with TMB-H cancer were
similar to those occurring in patients with other solid tumors who
received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with cSCC were similar
to those occurring in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy.
In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel,
paclitaxel protein-bound, or gemcitabine and carboplatin) were
administered to patients with locally recurrent unresectable or
metastatic TNBC (n=596) who had not been previously treated with
chemotherapy in the metastatic setting, fatal adverse reactions
occurred in 2.5% of patients, including cardio-respiratory arrest
(0.7%) and septic shock (0.3%). Serious adverse reactions occurred
in 30% of patients receiving KEYTRUDA in combination with
chemotherapy, the most common were: pneumonia (2.9%), anemia
(2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11%
of patients due to adverse reactions. The most common adverse
reactions resulting in permanent discontinuation (≥1%) were
increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%).
The most common adverse reactions (≥20%) in patients receiving
KEYTRUDA in combination with chemotherapy were: fatigue (48%),
nausea (44%), alopecia (34%), diarrhea and constipation (28% each),
vomiting and rash (26% each), cough (23%), decreased appetite
(21%), and headache (20%).
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
and for 4 months after the final dose.
Pediatric Use
In KEYNOTE-051, 161 pediatric patients (62 pediatric patients
aged 6 months to younger than 12 years and 99 pediatric patients
aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every
3 weeks. The median duration of exposure was 2.1 months (range: 1
day to 24 months).
Adverse reactions that occurred at a ≥10% higher rate in
pediatric patients when compared to adults were pyrexia (33%),
vomiting (30%), leukopenia (30%), upper respiratory tract infection
(29%), neutropenia (26%), headache (25%), and Grade 3 anemia
(17%).
Please see Prescribing Information for KEYTRUDA
(pembrolizumab) at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
About LENVIMA® (lenvatinib) Capsules
LENVIMA® (lenvatinib) is a kinase inhibitor that is
indicated:
- For the treatment of patients with locally recurrent or
metastatic, progressive, radioactive iodine-refractory
differentiated thyroid cancer (DTC)
- In combination with everolimus, for the treatment of patients
with advanced renal cell carcinoma (RCC) following one prior
anti-angiogenic therapy
- For the first-line treatment of patients with unresectable
hepatocellular carcinoma (HCC)
- In combination with KEYTRUDA, for the treatment of patients
with advanced endometrial carcinoma (EC) that is not microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR), who
have disease progression following prior systemic therapy, and are
not candidates for curative surgery or radiation. 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 trial
LENVIMA, discovered and developed by Eisai, is a kinase
inhibitor that inhibits the kinase activities of vascular
endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2
(KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have
been implicated in pathogenic angiogenesis, tumor growth, and
cancer progression in addition to their normal cellular functions,
including fibroblast growth factor (FGF) receptors FGFR1-4,
platelet derived growth factor receptor alpha (PDGFRα), KIT, and
RET. Lenvatinib also exhibited antiproliferative activity in
hepatocellular carcinoma cell lines dependent on activated FGFR
signaling with a concurrent inhibition of FGD-receptor substrate 2
alpha (FRS2α) phosphorylation. The combination of lenvatinib and
everolimus showed increased anti-angiogenic and anti-tumor activity
as demonstrated by decreases in human endothelial cell
proliferation, tube formation, and VEGF signaling in vitro and
decreases in tumor volume in mouse xenograft models of human renal
cell cancer greater than those with either drug alone. In syngeneic
mouse tumor models, lenvatinib decreased tumor-associated
macrophages, increased activated cytotoxic T cells, and
demonstrated greater antitumor activity in combination with an
anti-PD-1 monoclonal antibody compared to either treatment
alone.
Selected Safety Information for LENVIMA
Warnings and Precautions
Hypertension. In DTC, hypertension occurred in 73% of
patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred
in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic
blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had
diastolic blood pressure ≥100 mmHg. In HCC, hypertension occurred
in 45% of LENVIMA-treated patients (24% grade 3). Grade 4
hypertension was not reported in HCC.
Serious complications of poorly controlled hypertension have
been reported. Control blood pressure prior to initiation. Monitor
blood pressure after 1 week, then every 2 weeks for the first 2
months, and then at least monthly thereafter during treatment.
Withhold and resume at reduced dose when hypertension is controlled
or permanently discontinue based on severity.
Cardiac Dysfunction. Serious and fatal cardiac
dysfunction can occur with LENVIMA. Across clinical trials in 799
patients with DTC, RCC, and HCC, grade 3 or higher cardiac
dysfunction occurred in 3% of LENVIMA treated patients. Monitor for
clinical symptoms or signs of cardiac dysfunction. Withhold and
resume at reduced dose upon recovery or permanently discontinue
based on severity.
Arterial Thromboembolic Events. Among patients receiving
LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of
any severity occurred in 2% of patients in RCC and HCC and 5% in
DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3%
across all clinical trials. Permanently discontinue following an
arterial thrombotic event. The safety of resuming after an arterial
thromboembolic event has not been established and LENVIMA has not
been studied in patients who have had an arterial thromboembolic
event within the previous 6 months.
Hepatotoxicity. Across clinical studies enrolling 1,327
LENVIMA-treated patients with malignancies other than HCC, serious
hepatic adverse reactions occurred in 1.4% of patients. Fatal
events, including hepatic failure, acute hepatitis and hepatorenal
syndrome, occurred in 0.5% of patients. In HCC, hepatic
encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade
3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated
patients. 2% of patients discontinued LENVIMA due to hepatic
encephalopathy and 1% discontinued due to hepatic failure.
Monitor liver function prior to initiation, then every 2 weeks
for the first 2 months, and at least monthly thereafter during
treatment. Monitor patients with HCC closely for signs of hepatic
failure, including hepatic encephalopathy. Withhold and resume at
reduced dose upon recovery or permanently discontinue based on
severity.
Renal Failure or Impairment. Serious including fatal
renal failure or impairment can occur with LENVIMA. Renal
impairment was reported in 14% and 7% of LENVIMA-treated patients
in DTC and HCC, respectively. Grade 3-5 renal failure or impairment
occurred in 3% of patients with DTC and 2% of patients with HCC,
including 1 fatal event in each study. In RCC, renal impairment or
renal failure was reported in 18% of LENVIMA + everolimus–treated
patients (10% grade 3).
Initiate prompt management of diarrhea or
dehydration/hypovolemia. Withhold and resume at reduced dose upon
recovery or permanently discontinue for renal failure or impairment
based on severity.
Proteinuria. In DTC and HCC, proteinuria was reported in
34% and 26% of LENVIMA-treated patients, respectively. Grade 3
proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In
RCC, proteinuria occurred in 31% of patients receiving LENVIMA +
everolimus (8% grade 3). Monitor for proteinuria prior to
initiation and periodically during treatment. If urine dipstick
proteinuria ≥2+ is detected, obtain a 24-hour urine protein.
Withhold and resume at reduced dose upon recovery or permanently
discontinue based on severity.
Diarrhea. Of the 737 LENVIMA-treated patients in DTC and
HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea
occurred in 81% of LENVIMA + everolimus–treated patients (19% grade
3). Diarrhea was the most frequent cause of dose
interruption/reduction, and diarrhea recurred despite dose
reduction. Promptly initiate management of diarrhea. Withhold and
resume at reduced dose upon recovery or permanently discontinue
based on severity.
Fistula Formation and Gastrointestinal Perforation. Of
the 799 patients treated with LENVIMA or LENVIMA + everolimus in
DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred
in 2%. Permanently discontinue in patients who develop
gastrointestinal perforation of any severity or grade 3-4
fistula.
QT Interval Prolongation. In DTC, QT/QTc interval
prolongation occurred in 9% of LENVIMA-treated patients and QT
interval prolongation of >500 ms occurred in 2%. In RCC, QTc
interval increases of >60 ms occurred in 11% of patients
receiving LENVIMA + everolimus and QTc interval >500 ms occurred
in 6%. In HCC, QTc interval increases of >60 ms occurred in 8%
of LENVIMA-treated patients and QTc interval >500 ms occurred in
2%.
Monitor and correct electrolyte abnormalities at baseline and
periodically during treatment. Monitor electrocardiograms in
patients with congenital long QT syndrome, congestive heart
failure, bradyarrhythmias, or those who are taking drugs known to
prolong the QT interval, including Class Ia and III
antiarrhythmics. Withhold and resume at reduced dose upon recovery
based on severity.
Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in
9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia
improved or resolved following calcium supplementation with or
without dose interruption or dose reduction. In RCC, grade 3-4
hypocalcemia occurred in 6% of LENVIMA + everolimus– treated
patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of
LENVIMA-treated patients. Monitor blood calcium levels at least
monthly and replace calcium as necessary during treatment. Withhold
and resume at reduced dose upon recovery or permanently discontinue
depending on severity.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS).
Across clinical studies of 1,823 patients who received LENVIMA as a
single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with
MRI. Withhold and resume at reduced dose upon recovery or
permanently discontinue depending on severity and persistence of
neurologic symptoms.
Hemorrhagic Events. Serious including fatal hemorrhagic
events can occur with LENVIMA. In DTC, RCC, and HCC clinical
trials, hemorrhagic events, of any grade, occurred in 29% of the
799 patients treated with LENVIMA as a single agent or in
combination with everolimus. The most frequently reported
hemorrhagic events (all grades and occurring in at least 5% of
patients) were epistaxis and hematuria. In DTC, grade 3-5
hemorrhage occurred in 2% of LENVIMA-treated patients, including 1
fatal intracranial hemorrhage among 16 patients who received
LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5
hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients,
including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage
occurred in 5% of LENVIMA-treated patients, including 7 fatal
hemorrhagic events. Serious tumor-related bleeds, including fatal
hemorrhagic events, occurred in LENVIMA-treated patients in
clinical trials and in the postmarketing setting. In postmarketing
surveillance, serious and fatal carotid artery hemorrhages were
seen more frequently in patients with anaplastic thyroid carcinoma
(ATC) than other tumors. Safety and effectiveness of LENVIMA in
patients with ATC have not been demonstrated in clinical
trials.
Consider the risk of severe or fatal hemorrhage associated with
tumor invasion or infiltration of major blood vessels (e.g.,
carotid artery). Withhold and resume at reduced dose upon recovery
or permanently discontinue based on severity.
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid
Dysfunction. LENVIMA impairs exogenous thyroid suppression. In
DTC, 88% of patients had baseline thyroid stimulating hormone (TSH)
level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation
of TSH level >0.5 mU/L was observed post baseline in 57% of
LENVIMA-treated patients. In RCC and HCC, grade 1 or 2
hypothyroidism occurred in 24% of LENVIMA + everolimus–treated
patients and 21% of LENVIMA-treated patients, respectively. In
patients with normal or low TSH at baseline, elevation of TSH was
observed post baseline in 70% of LENVIMA-treated patients in HCC
and 60% of LENVIMA + everolimus–treated patients in RCC.
Monitor thyroid function prior to initiation and at least
monthly during treatment. Treat hypothyroidism according to
standard medical practice.
Impaired Wound Healing. Impaired wound healing has been
reported in patients who received LENVIMA. Withhold LENVIMA for at
least 1 week prior to elective surgery. Do not administer for at
least 2 weeks following major surgery and until adequate wound
healing. The safety of resumption of LENVIMA after resolution of
wound healing complications has not been established.
Osteonecrosis of the Jaw (ONJ). ONJ has been reported in
patients receiving LENVIMA. Concomitant exposure to other risk
factors, such as bisphosphonates, denosumab, dental disease, or
invasive dental procedures, may increase the risk of ONJ.
Perform an oral examination prior to treatment with LENVIMA and
periodically during LENVIMA treatment. Advise patients regarding
good oral hygiene practices and to consider having preventive
dentistry performed prior to treatment with LENVIMA and throughout
treatment with LENVIMA.
Avoid invasive dental procedures, if possible, while on LENVIMA
treatment, particularly in patients at higher risk. Withhold
LENVIMA for at least 1 week prior to scheduled dental surgery or
invasive dental procedures, if possible. For patients requiring
invasive dental procedures, discontinuation of bisphosphonate
treatment may reduce the risk of ONJ.
Withhold LENVIMA if ONJ develops and restart based on clinical
judgement of adequate resolution.
Embryo-fetal Toxicity. Based on its mechanism of action
and data from animal reproduction studies, LENVIMA can cause fetal
harm when administered to pregnant women. In animal reproduction
studies, oral administration of lenvatinib during organogenesis at
doses below the recommended clinical doses resulted in
embryotoxicity, fetotoxicity, and teratogenicity in rats and
rabbits. Advise pregnant women of the potential risk to a fetus;
and advise females of reproductive potential to use effective
contraception during treatment with LENVIMA and for at least 30
days after the last dose.
Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in
LENVIMA-treated patients were hypertension (73%), fatigue (67%),
diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%),
decreased weight (51%), nausea (47%), stomatitis (41%), headache
(38%), vomiting (36%), proteinuria (34%), palmar-plantar
erythrodysesthesia syndrome (32%), abdominal pain (31%), and
dysphonia (31%). The most common serious adverse reactions (≥2%)
were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of LENVIMA-treated
patients; 18% discontinued LENVIMA. The most common adverse
reactions (≥10%) resulting in dose reductions were hypertension
(13%), proteinuria (11%), decreased appetite (10%), and diarrhea
(10%); the most common adverse reactions (≥1%) resulting in
discontinuation of LENVIMA were hypertension (1%) and asthenia
(1%).
In RCC, the most common adverse reactions (≥30%) observed in
LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue
(73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting
(48%), nausea (45%), stomatitis (44%), hypertension (42%),
peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea
(35%), rash (35%), decreased weight (34%), hemorrhagic events
(32%), and proteinuria (31%). The most common serious adverse
reactions (≥5%) were renal failure (11%), dehydration (10%), anemia
(6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and
dyspnea (5%). Adverse reactions led to dose reductions or
interruption in 89% of patients. The most common adverse reactions
(≥5%) resulting in dose reductions were diarrhea (21%), fatigue
(8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and
proteinuria (5%). Treatment discontinuation due to an adverse
reaction occurred in 29% of patients.
In HCC, the most common adverse reactions (≥20%) observed in
LENVIMA-treated patients were hypertension (45%), fatigue (44%),
diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%),
decreased weight (31%), abdominal pain (30%), palmar-plantar
erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia
(24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea
(20%). The most common serious adverse reactions (≥2%) were hepatic
encephalopathy (5%), hepatic failure (3%), ascites (3%), and
decreased appetite (2%). Adverse reactions led to dose reductions
or interruption in 62% of patients. The most common adverse
reactions (≥5%) resulting in dose reductions were fatigue (9%),
decreased appetite (8%), diarrhea (8%), proteinuria (7%),
hypertension (6%), and palmar-plantar erythrodysesthesia syndrome
(5%). Treatment discontinuation due to an adverse reaction occurred
in 20% of patients. The most common adverse reactions (≥1%)
resulting in discontinuation of LENVIMA were fatigue (1%), hepatic
encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure
(1%).
In EC, the most common adverse reactions (≥20%) observed in
LENVIMA + pembrolizumab - treated patients were fatigue (65%),
hypertension (65%), musculoskeletal pain (65%), diarrhea (64%),
decreased appetite (52%), hypothyroidism (51%), nausea (48%),
stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal
pain (33%), headache (33%), constipation (32%), urinary tract
infection (31%), dysphonia (29%), hemorrhagic events (28%),
hypomagnesemia (27%), palmar-plantar erythrodysesthesia (26%),
dyspnea (24%), cough (21%) and rash (21%). Adverse reactions led to
dose reduction or interruption in 88% of patients receiving
LENVIMA. The most common adverse reactions (≥5%) resulting in dose
reduction or interruption of LENVIMA were fatigue (32%),
hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar
erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%),
musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%),
hemorrhages (7%), renal impairment (6%), decreased weight (6%),
rash (5%), headache (5%), increased lipase (5%) and proteinuria
(5%). Fatal adverse reactions occurred in 3% of patients receiving
LENVIMA + pembrolizumab, including gastrointestinal perforation,
RPLS with intraventricular hemorrhage, and intracranial hemorrhage.
Serious adverse reactions occurred in 52% of patients receiving
LENVIMA + pembrolizumab. Serious adverse reactions in ≥3% of
patients were hypertension (9%), abdominal pain (6%),
musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea
(4%), confusional state (4%), pleural effusion (4%), adrenal
insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).
Permanent discontinuation due to adverse reaction (Grade 1-4)
occurred in 21% of patients who received LENVIMA + pembrolizumab.
The most common adverse reactions (>2%) resulting in
discontinuation of LENVIMA were gastrointestinal perforation or
fistula (2%), muscular weakness (2%), and pancreatitis (2%).
Use in Specific Populations
Because of the potential for serious adverse reactions in
breastfed infants, advise women to discontinue breastfeeding during
treatment and for at least 1 week after last dose. LENVIMA may
impair fertility in males and females of reproductive
potential.
No dose adjustment is recommended for patients with mild (CLcr
60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment.
LENVIMA concentrations may increase in patients with DTC, RCC or EC
and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose
for patients with DTC, RCC, or EC and severe renal impairment.
There is no recommended dose for patients with HCC and severe renal
impairment. LENVIMA has not been studied in patients with end stage
renal disease. No dose adjustment is recommended for patients with
HCC and mild hepatic impairment (Child-Pugh A). There is no
recommended dose for patients with HCC with moderate (Child-Pugh B)
or severe (Child-Pugh C) hepatic impairment.
No dose adjustment is recommended for patients with DTC, RCC, or
EC and mild or moderate hepatic impairment. LENVIMA concentrations
may increase in patients with DTC, RCC, or EC and severe hepatic
impairment. Reduce the dose for patients with DTC, RCC, or EC and
severe hepatic impairment.
LENVIMA (lenvatinib) is available as 10 mg and 4 mg
capsules.
Please see Prescribing Information for LENVIMA (lenvatinib)
at http://www.lenvima.com/pdfs/prescribing-information.pdf.
About the Merck and Eisai Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United
States and Canada, through an affiliate, entered into a strategic
collaboration for the worldwide co-development and
co-commercialization of LENVIMA. Under the agreement, the companies
will jointly develop, manufacture and commercialize LENVIMA, both
as monotherapy and in combination with Merck’s anti-PD-1 therapy
KEYTRUDA.
In addition to ongoing clinical studies evaluating the KEYTRUDA
plus LENVIMA combination across several different tumor types, the
companies have jointly initiated new clinical studies through the
LEAP (LEnvatinib And Pembrolizumab) clinical program and are
evaluating the combination in 14 different tumor types (endometrial
carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung
cancer, renal cell carcinoma, squamous cell carcinoma of the head
and neck, urothelial cancer, biliary tract cancer, colorectal
cancer, gastric cancer, glioblastoma, ovarian cancer, pancreatic
cancer and triple-negative breast cancer) across more than 20
clinical trials.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For 130 years, Merck, 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 in
pursuit of our mission to save and improve lives. We demonstrate
our commitment to patients and population health by increasing
access to health care through far-reaching policies, programs and
partnerships. Today, Merck continues to be at the forefront of
research to prevent and treat diseases that threaten people and
animals – including cancer, infectious diseases such as HIV and
Ebola, and emerging animal diseases – as we aspire to be the
premier research-intensive biopharmaceutical company in the world.
For more information, visit www.merck.com and connect with us on
Twitter, Facebook, Instagram, YouTube and LinkedIn.
Eisai’s Focus on Cancer
Eisai focuses on the development of anticancer drugs, targeting
the tumor microenvironment (with experience and knowledge from
existing in-house discovered compounds) and the driver gene
mutation and aberrant splicing (leveraging RNA Splicing Platform)
as areas (Ricchi) where real patient needs are still unmet, and
where Eisai can aim to become a frontrunner in oncology. Eisai
aspires to discover innovative new drugs with new targets and
mechanisms of action from these Ricchi, with the aim of
contributing to the cure of cancers.
About Eisai
Eisai is a leading global research and development-based
pharmaceutical company headquartered in Japan, with approximately
10,000 employees worldwide. 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. We strive to realize our hhc
philosophy by delivering innovative products in therapeutic areas
with high unmet medical needs, including Oncology and Neurology. In
the spirit of hhc, we take that commitment even further by applying
our scientific expertise, clinical capabilities and patient
insights to discover and develop innovative solutions that help
address society’s toughest unmet needs, including neglected
tropical diseases and the Sustainable Development Goals.
For more information about Eisai, please visit www.eisai.com
(for global), us.eisai.com (for U.S.) or www.eisai.eu (for Europe,
Middle East, Africa), and connect with us on Twitter (U.S. and
global) and LinkedIn (for U.S.).
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 the global outbreak of novel coronavirus disease
(COVID-19); 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 2020
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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version on businesswire.com: https://www.businesswire.com/news/home/20210607005121/en/
Merck Media Relations Melissa Moody: (215) 407-3536
Justine Moore: (347) 281-3754
Merck Investor Relations Peter Dannenbaum: (908) 740-1037
Courtney Ronaldo: (908) 740-6132
Eisai Inc. Media Relations Michele Randazzo: (551)
579-4465
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