European Medicines Agency Adopts Positive Opinion for Merck’s KEYTRUDA® (pembrolizumab) in Combination with Chemotherapy for First-Line Treatment of Adults with Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)

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February 4, 2019 6:45 am ET

Recommendation Based on Significant Overall Survival Benefit Demonstrated with KEYTRUDA in Combination with Chemotherapy in Pivotal KEYNOTE-407 Trial

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the Committee for Medicinal Products for Human Use
(CHMP) of the European Medicines Agency (EMA) has adopted a positive
opinion recommending KEYTRUDA, Merck’s anti-PD-1 therapy, in combination
with carboplatin and either paclitaxel or nab-paclitaxel, for the
first-line treatment of metastatic squamous non-small cell lung cancer
(NSCLC) in adults. This recommendation is based on results from the
pivotal, Phase 3 KEYNOTE-407 trial, which enrolled patients regardless
of PD-L1 tumor expression status. The trial showed a significant
improvement in overall survival (OS) and progression-free survival (PFS)
for patients taking KEYTRUDA in combination with chemotherapy
(carboplatin and either paclitaxel or nab-paclitaxel) compared with
chemotherapy alone. If approved, this would mark the first approval in
Europe for an anti-PD-1 therapy in combination with chemotherapy for
adults with metastatic squamous NSCLC.

“We are pleased by today’s positive opinion from the CHMP, which brings
us one step closer to potentially expanding our lung cancer indications
in Europe to include first-line combination therapy for patients with
metastatic squamous non-small cell lung cancer, regardless of PD-L1
expression,” said Dr. Roy Baynes, senior vice president and head of
global clinical development, chief medical officer, Merck Research
Laboratories. “This is important as squamous cell carcinoma continues to
be an area of unmet need, and there was a significant overall survival
benefit observed in the Phase 3 KEYNOTE-407 trial.”

Data from KEYNOTE-407 were presented at the 2018 American Society of
Clinical Oncology (ASCO) Annual Meeting and were published in The New
England Journal of Medicine. The CHMP’s recommendation will now be
reviewed by the European Commission for marketing authorization in the
European Union (EU). The decision by the European Commission is expected
in the first quarter of 2019.

KEYNOTE-407 is part of Merck’s leading clinical development program in
lung cancer, which includes 10 Merck-sponsored Phase 3 trials. These
trials are evaluating KEYTRUDA in combination with other treatments and
as monotherapy, in both advanced and earlier stages of disease, as well
as across different histologies and lines of treatment.

About Lung Cancer in Europe

Lung cancer, which forms in the tissues of the lungs, usually within
cells lining the air passages, is the leading cause of cancer death in
Europe and worldwide. In 2018, there were nearly 388,000 deaths from
lung cancer in Europe. The two main types of lung cancer are non-small
cell and small cell. NSCLC is the most common type of lung cancer,
accounting for about 85 percent of all cases. There are several subtypes
of NSCLC, including adenocarcinoma (accounting for 40 percent of lung
cancers), squamous cell carcinoma (25 to 30 percent) and large cell
carcinoma (10 to 15 percent).

About KEYTRUDA
^®
(pembrolizumab) Injection,
100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of
the body’s immune system to help detect and fight tumor cells. KEYTRUDA
is a humanized monoclonal antibody that blocks the interaction between
PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes
which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research
program. There are currently more than 900 trials studying KEYTRUDA
across a wide variety of cancers and treatment settings. The KEYTRUDA
clinical program seeks to understand the role of KEYTRUDA across cancers
and the factors that may predict a patient’s likelihood of benefitting
from treatment with KEYTRUDA, including exploring several different
biomarkers.

KEYTRUDA
^®
(pembrolizumab) Indications and
Dosing in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a fixed dose of 200 mg every three weeks until
disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, 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
nab-paclitaxel, 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 metastatic NSCLC whose tumors have high PD-L1
expression [Tumor Proportion Score (TPS) ≥50%] as determined by an
FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is 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.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA
should be administered prior to chemotherapy when given on the same day.
See also the Prescribing Information for the chemotherapy agents
administered in combination with KEYTRUDA, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC) with disease
progression on or after platinum-containing chemotherapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is
administered at a fixed dose of 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory classical Hodgkin lymphoma (cHL), or who have relapsed
after 3 or more prior lines of therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. In adults with cHL, KEYTRUDA is administered at a
fixed dose of 200 mg every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with cHL, KEYTRUDA is administered at
a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.

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. 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 confirmatory trials. KEYTRUDA is not recommended for
the treatment of patients with PMBCL who require urgent cytoreductive
therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression. In pediatric
patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up
to a maximum of 200 mg) every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not eligible
for cisplatin-containing chemotherapy and whose tumors express PD-L1
[Combined Positive Score (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 the 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.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is
administered at a fixed dose of 200 mg every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in patients
without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with unresectable or metastatic microsatellite instability-high (MSI-H)
or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who
have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with
fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The safety and
effectiveness of KEYTRUDA in pediatric patients with MSI-H central
nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed
dose of 200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression. In
children with MSI-H cancer, KEYTRUDA is administered at a dose of 2
mg/kg (up to a maximum of 200 mg) every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in patients
without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent
locally advanced or metastatic gastric or gastroesophageal junction
(GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score
(CPS) ≥1] as determined by an FDA-approved test, with disease
progression on or after two or more prior lines of therapy including
fluoropyrimidine- and platinum-containing chemotherapy and if
appropriate, HER2/neu-targeted therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of
200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease progression.

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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every
three weeks until disease progression, unacceptable toxicity, or up to
24 months in patients without disease progression.

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. The recommended dose of
KEYTRUDA is a fixed dose of 200 mg every three weeks until disease
progression, unacceptable toxicity, or up to 24 months in patients
without disease progression.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with recurrent locally advanced or metastatic Merkel cell carcinoma.
This indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. The recommended dose of
KEYTRUDA in adults is 200 mg administered as an intravenous infusion
over 30 minutes every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without disease
progression. The recommended dose of KEYTRUDA in pediatric patients is 2
mg/kg (up to a maximum of 200 mg), administered as an intravenous
infusion over 30 minutes every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.
Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA,
including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%),
and occurred more frequently in patients with a history of prior
thoracic radiation (6.9%) compared to those without (2.9%). Monitor
patients for signs and symptoms of pneumonitis. Evaluate suspected
pneumonitis with radiographic imaging. Administer corticosteroids for
Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2;
permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2
pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7%
(48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3
(1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of
colitis. Administer corticosteroids for Grade 2 or greater colitis.
Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for
Grade 4 colitis.

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7%
(19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.4%), and 4 (<0.1%). Monitor patients for changes in liver function.
Administer corticosteroids for Grade 2 or greater hepatitis and, based
on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes
mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including
Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5%
(237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The
incidence of new or worsening hypothyroidism was higher in patients with
HNSCC, occurring in 15% (28/192) of patients. Hyperthyroidism occurred
in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%),
and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade
2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis,
occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including
hypopituitarism and adrenal insufficiency), thyroid function (prior to
and periodically during treatment), and hyperglycemia. For hypophysitis,
administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for
Grade 3 or 4 hypophysitis. Administer hormone replacement for
hypothyroidism and manage hyperthyroidism with thionamides and
beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade
3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and
withhold KEYTRUDA and administer antihyperglycemics in patients with
severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3%
(9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of
patients receiving KEYTRUDA in combination with pemetrexed and platinum
chemotherapy. Monitor patients for changes in renal function. Administer
corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for
Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative
dermatitis, and bullous pemphigoid, can occur. Monitor patients for
suspected severe skin reactions and based on the severity of the adverse
reaction, withhold or permanently discontinue KEYTRUDA and administer
corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA
and refer the patient for specialized care for assessment and treatment.
If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue in patients receiving KEYTRUDA and
may also occur after discontinuation of treatment. For suspected
immune-mediated adverse reactions, ensure adequate evaluation to confirm
etiology or exclude other causes. Based on the severity of the adverse
reaction, withhold KEYTRUDA and administer corticosteroids. Upon
improvement to Grade 1 or less, initiate corticosteroid taper and
continue to taper over at least 1 month. Based on limited data from
clinical studies in patients whose immune-related adverse reactions
could not be controlled with corticosteroid use, administration of other
systemic immunosuppressants can be considered. Resume KEYTRUDA when the
adverse reaction remains at Grade 1 or less following corticosteroid
taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated
adverse reaction that recurs and for any life-threatening
immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions
occurred in less than 1% (unless otherwise indicated) of 2799 patients:
arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia
gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and
encephalitis. In addition, myelitis and myocarditis were reported in
other clinical trials and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid
organ transplant recipients. Consider the benefit of treatment vs the
risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have been
reported in 0.2% (6/2799) of patients. Monitor patients for signs and
symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop
infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT)

Immune-mediated complications, including fatal events, occurred in
patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of
23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6
developed graft-versus-host disease (GVHD) (1 fatal case) and 2
developed severe hepatic veno-occlusive disease (VOD) after
reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute
GVHD after allogeneic HSCT have also been reported in patients with
lymphoma who received a PD-1 receptor–blocking antibody before
transplantation. Follow patients closely for early evidence of
transplant-related complications such as hyperacute graft-versus-host
disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile
syndrome, hepatic veno-occlusive disease (VOD), and other
immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including
fatal GVHD) has been reported after treatment with KEYTRUDA. Patients
who experienced GVHD after their transplant procedure may be at
increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA
vs the risk of GVHD in these patients.

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 a PD-1 or PD-L1 blocking
antibody 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-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 nab-paclitaxel 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-010, KEYTRUDA monotherapy was discontinued due to adverse
reactions in 8% of 682 patients with metastatic NSCLC. The most common
adverse event resulting in permanent discontinuation of KEYTRUDA was
pneumonitis (1.8%). The most common adverse reactions (≥20%) were
decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

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-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% included 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%).

Adverse reactions occurring in patients with gastric cancer 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%).

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

There is limited experience in pediatric patients. In a trial, 40
pediatric patients (16 children aged 2 years to younger than 12 years
and 24 adolescents aged 12 years to 18 years) with various cancers,
including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3
weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17
doses), with 34 patients (85%) receiving 2 doses or more. The safety
profile in these pediatric patients was similar to that seen in adults;
adverse reactions that occurred at a higher rate (≥15% difference) in
these patients when compared to adults under 65 years of age were
fatigue (45%), vomiting (38%), abdominal pain (28%), increased
transaminases (28%), and hyponatremia (18%).

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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.

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or delays; financial instability of international economies and
sovereign risk; dependence on the effectiveness of the company’s patents
and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause results
to differ materially from those described in the forward-looking
statements can be found in the company’s 2017 Annual Report on Form 10-K
and the company’s other filings with the Securities and Exchange
Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

###

Please see Prescribing Information for KEYTRUDA 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

.