KEYNOTE-522 Is the First Phase 3 Study With
an Immunotherapy to Show Positive EFS Results in High-Risk
Early-Stage Triple-Negative Breast Cancer
Merck Has Submitted These Data From
KEYNOTE-522 to the US FDA for Review
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced positive event-free survival (EFS) data
from the pivotal neoadjuvant/adjuvant Phase 3 study KEYNOTE-522.
The trial investigated neoadjuvant KEYTRUDA, Merck’s anti-PD-1
therapy, plus chemotherapy followed by adjuvant KEYTRUDA as
monotherapy (the KEYTRUDA regimen) compared with neoadjuvant
chemotherapy followed by adjuvant placebo (the chemotherapy-placebo
regimen) in patients with high-risk early-stage triple-negative
breast cancer (TNBC). This is the first time an anti-PD-1/L1
therapy has demonstrated a statistically significant EFS result as
combined neoadjuvant and adjuvant therapy for these patients. These
results are being presented today during a European Society for
Medical Oncology (ESMO) Virtual Plenary.
After a median follow-up of 39 months, the KEYTRUDA regimen
reduced the risk of EFS events by 37% (HR=0.63 [95% CI, 0.48-0.82];
p=0.00031) versus the chemotherapy-placebo regimen – a
statistically significant and clinically meaningful EFS result. EFS
was defined as the time from randomization to the first occurrence
of either disease progression that precluded definitive surgery, a
local/distant recurrence, a second primary cancer, or death from
any cause. As previously announced, KEYNOTE-522 met the dual
primary endpoint of pathological complete response (pCR) at the
first interim analysis. The trial is continuing to allow for
additional follow-up of overall survival (OS), a key secondary
endpoint. At this fourth interim analysis, although these data have
not crossed the boundary for statistical significance, there was a
28% reduction in the risk of death with the KEYTRUDA regimen versus
the chemotherapy-placebo regimen (HR=0.72 [95% CI, 0.51-1.02];
p=0.03214). The safety profile of the KEYTRUDA regimen was
consistent with the known profiles of each regimen, and no new
safety concerns were identified.
“Given the high rates of recurrence within the first five years
of diagnosis, patients with high-risk early-stage TNBC need new
treatment options,” said Dr. Peter Schmid, lead, Centre for
Experimental Cancer Medicine, Barts Cancer Institute in London,
England. “KEYNOTE-522 was designed to study whether the combined
neoadjuvant and adjuvant regimen with KEYTRUDA could help treat the
cancer earlier. Now, with more than three years of follow-up, we
see the potential of this approach. These event-free survival data
are very encouraging for patients and show that this combination of
KEYTRUDA plus chemotherapy as neoadjuvant therapy, followed by
single-agent KEYTRUDA as adjuvant therapy, may offer women with
high-risk early-stage TNBC a new treatment option for this
aggressive disease.”
“These highly anticipated event-free survival results in this
TNBC population build upon earlier findings from the KEYNOTE-522
trial and further support the potential use of KEYTRUDA in these
patients,” said Dr. Vicki Goodman, vice president, clinical
research, Merck Research Laboratories. “KEYNOTE-522 is the first
large randomized Phase 3 study to report a statistically
significant and clinically meaningful EFS result among patients
with stage II and stage III TNBC. We have submitted these data to
the FDA and are working closely with the agency on its review of
our application.”
KEYTRUDA is currently approved under accelerated approval in the
U.S. in combination with chemotherapy for the treatment of patients
with locally recurrent unresectable or metastatic TNBC whose tumors
express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by
an FDA-approved test.
Merck is rapidly advancing a broad portfolio in women’s cancers
with an extensive clinical development program for KEYTRUDA and
several other investigational and approved medicines across
multiple gynecologic and breast cancers. The KEYTRUDA clinical
development program for TNBC encompasses several internal studies
and external collaborative trials, including the ongoing studies
KEYNOTE-242 and KEYNOTE-355.
Study Design and Additional Data From KEYNOTE-522
KEYNOTE-522 is a Phase 3, randomized, double-blind trial
(ClinicalTrials.gov, NCT03036488). The dual primary endpoints are
pCR, defined as pathological stage ypT0/Tis ypN0 at the time of
definitive surgery, and EFS, defined as the time from randomization
to the first occurrence of either disease progression that
precluded definitive surgery, a local/distant recurrence, a second
primary cancer, or death from any cause in all patients randomized.
Secondary endpoints include pCR rate using alternative definitions,
OS in all patients randomized, pCR rate according to all
definitions, EFS and OS in patients whose tumors express PD-L1 (CPS
≥1), safety and health-related quality of life assessments. The
study enrolled 1,174 patients who were randomized 2:1 to receive
either:
- The KEYTRUDA regimen: KEYTRUDA (every three weeks) plus
paclitaxel (weekly) and carboplatin (weekly or every three weeks)
for four cycles, followed by KEYTRUDA plus cyclophosphamide and
either doxorubicin or epirubicin (every three weeks) for four
cycles as neoadjuvant therapy prior to surgery, followed by nine
cycles of KEYTRUDA (every three weeks) as adjuvant therapy
post-surgery (n=784)
- The chemotherapy-placebo regimen: Placebo (every three weeks)
plus paclitaxel (weekly) and carboplatin (weekly or every three
weeks) for four cycles, followed by placebo plus cyclophosphamide
and either doxorubicin or epirubicin (every three weeks) for four
cycles as neoadjuvant therapy prior to surgery, followed by nine
cycles of placebo (every three weeks) as adjuvant therapy
post-surgery (n=390)
As previously announced, KEYNOTE-522 met the success criterion
for the dual primary endpoint of pCR at the first interim analysis;
pCR was observed in 64.8% of patients treated with KEYTRUDA plus
chemotherapy (n=401), an increase of 13.6% (p=0.00055) from 51.2%
in patients treated with placebo plus chemotherapy (n=201). At the
fourth interim analysis, KEYNOTE-522 met the success criterion for
the dual primary endpoint of EFS. The study is continuing to allow
for additional follow-up of OS.
At three years, 84.5% of patients treated with the KEYTRUDA
regimen were alive and did not experience an EFS event compared to
76.8% of patients treated with the chemotherapy-placebo
regimen.
In pre-specified exploratory subgroup analyses of EFS, the EFS
benefit seen with the KEYTRUDA regimen was independent of PD-L1
expression. In the PD-L1-positive subgroup (n=973), defined as CPS
≥1, treatment with the KEYTRUDA regimen reduced the risk of EFS
events by 33% (HR=0.67 [95% CI, 0.49-0.92]) versus the
chemotherapy-placebo regimen. In the PD-L1-negative subgroup
(n=197), defined as CPS <1, treatment with the KEYTRUDA regimen
reduced the risk of EFS events by 52% (HR=0.48 [95% CI, 0.28-0.85])
versus the chemotherapy-placebo regimen.
In a pre-specified but non-randomized exploratory analysis of
EFS by pCR outcome, the reduction in EFS events with the KEYTRUDA
regimen was observed independent of pCR outcome at definitive
surgery.
Treatment-related adverse events (TRAEs) were examined in the
neoadjuvant phase, the adjuvant phase and the combined phases.
TRAEs in the neoadjuvant phase have been previously reported. At
the time of this data cutoff, no patients were still receiving
protocol treatment. For the combined neoadjuvant and adjuvant
phases, TRAEs occurred in 98.9% of patients receiving the KEYTRUDA
regimen (n=783) and 99.7% of patients receiving the
chemotherapy-placebo regimen (n=389); Grade 3-5 TRAEs occurred in
77.1% versus 73.3%, respectively. TRAEs led to death in 0.5% of
patients receiving the KEYTRUDA regimen (n=4) and 0.3% of patients
receiving the chemotherapy-placebo regimen (n=1). No new safety
concerns were identified. In the adjuvant phase, TRAEs occurred in
53.7% of patients receiving adjuvant KEYTRUDA (n=588) and 48.6% of
patients receiving adjuvant placebo (n=331), including 6.3% and
2.7%, respectively, who had at least one Grade ≥3 event.
Immune-mediated adverse events (AEs) and infusion reactions of
any grade in the combined neoadjuvant and adjuvant phases occurred
in 43.6% of patients receiving the KEYTRUDA regimen and 21.9% of
patients receiving the chemotherapy-placebo regimen. The most
common of these events (occurring in ≥10% of patients) were
infusion reactions (18.0%) and hypothyroidism (15.1%) in patients
receiving the KEYTRUDA regimen and infusion reactions (11.6%) in
patients receiving the chemotherapy-placebo regimen.
Immune-mediated AEs led to death in 0.3% of patients receiving the
KEYTRUDA regimen (n=2) and no patients receiving the
chemotherapy-placebo regimen. In the adjuvant phase,
immune-mediated AEs and infusion reactions occurred in 10.2% of
patients receiving adjuvant KEYTRUDA and 6.0% of patients receiving
adjuvant placebo, including 2.9% and 0.3%, respectively, who had at
least one Grade ≥3 event.
About Triple-Negative Breast Cancer (TNBC)
Triple-negative breast cancer is an aggressive type of breast
cancer that characteristically has a high recurrence rate within
the first five years after diagnosis. While some breast cancers may
test positive for estrogen receptors, progesterone receptors or
overexpression of human epidermal growth factor receptor 2 (HER2),
TNBC tests negative for all three. Approximately 10-15% of patients
with breast cancer are diagnosed with TNBC. TNBC tends to be more
common in people who are younger than 40 years of age, who are
African American or who have a BRCA1 mutation.
About KEYTRUDA® (pembrolizumab) Injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (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 1,500 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 (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 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-unresponsive, high-risk, non-muscle
invasive bladder cancer (NMIBC) with carcinoma in situ 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.
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 treatment of patients with
unresectable or metastatic MSI-H or dMMR colorectal cancer
(CRC).
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, 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.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic esophageal or 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.
Tumor Mutational Burden-High Cancer
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) or
locally advanced 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% 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, 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) of patients. 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+ gastric or 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 (reported in ≥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.
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 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%).
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 recurrent or
metastatic cSCC or locally advanced 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 who had not been previously treated with
chemotherapy in the metastatic setting (n=596), 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 serious reactions in ≥2% were
pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).
KEYTRUDA was discontinued in 11% of patients due to adverse
reactions. The most common 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%).
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
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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).
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.
View source
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Media: Melissa Moody (215) 407-3536 Ayn Wisler (908) 740-5590
Investors: Peter Dannenbaum (908) 740-1037 Courtney Ronaldo (908)
740-6132
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