Merck’s KEYTRUDA® (pembrolizumab) Significantly Improved Overall Survival (OS) Compared to Chemotherapy in Patients with Advanced Esophageal or Esophagogastric Junction Carcinoma Whose Tumors Express PD-L1 (CPS ≥10)

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November 14, 2018 6:45 am ET

With Pivotal KEYNOTE-181 Trial Meeting Primary Endpoint of OS, KEYTRUDA Becomes the First Anti-PD-1 Therapy to Demonstrate a Survival Benefit for These Patients

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that the Phase 3 KEYNOTE-181 trial investigating
KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy in the second-line
treatment of advanced or metastatic esophageal or esophagogastric
junction carcinoma has met a primary endpoint of overall survival (OS)
in patients whose tumors expressed PD-L1 (Combined Positive Score [CPS]
≥10). In this pivotal study, treatment with KEYTRUDA resulted in a
statistically significant improvement in OS compared to chemotherapy
(paclitaxel, docetaxel or irinotecan) in patients with CPS ≥10,
regardless of histology. The primary endpoint of OS was also evaluated
in patients with squamous cell histology and in the entire
intention-to-treat (ITT) study population. While directionally
favorable, statistical significance for OS was not met in these two
patient groups. Per the statistical analysis plan, the key secondary
endpoints of progression-free survival (PFS) and objective response rate
(ORR) were not formally tested, as OS was not reached in the full ITT
study population. The safety profile of KEYTRUDA in this trial was
consistent with that observed in previously reported studies. Results
will be presented at an upcoming medical meeting and will be submitted
to regulatory authorities worldwide.

“In this pivotal trial, KEYTRUDA resulted in a statistically significant
and clinically meaningful improvement over standard chemotherapy in
overall survival for patients with advanced esophageal or
esophagogastric junction carcinoma whose tumors express PD-L1 with a CPS
of 10 or greater. This marks the sixth tumor type where KEYTRUDA has
demonstrated a survival benefit, and represents the first time an
anti-PD-1 therapy has achieved overall survival for this patient
population,” said Dr. Roy Baynes, senior vice president and head of
global clinical development, chief medical officer, Merck Research
Laboratories. “We are encouraged by these results of KEYTRUDA as
monotherapy in previously-treated patients, and look forward to
continuing our research efforts in this significant area of unmet need
with our ongoing Phase 3 trial, KEYNOTE-590, evaluating KEYTRUDA in
combination with chemotherapy as a first-line treatment for patients
with esophageal carcinoma.”

About KEYNOTE-181

KEYNOTE-181 is a randomized, open-label,
Phase 3 trial (ClinicalTrials.gov, NCT02564263)
investigating KEYTRUDA monotherapy compared to chemotherapy in patients
with advanced or metastatic adenocarcinoma or squamous cell carcinoma of
the esophagus, or Siewert type I adenocarcinoma of the esophagogastric
junction that has progressed after first-line standard therapy. The
primary endpoint was OS (evaluated in all patients as well as in
patients with PD-L1 CPS ≥10 and in patients with squamous cell
carcinoma). Secondary endpoints were PFS, ORR and safety/tolerability.
The study enrolled more than 600 patients who were randomized 1:1 to
receive either KEYTRUDA (200 mg fixed dose every three weeks) or
investigator’s choice of any of the following chemotherapy regimens, all
given intravenously: docetaxel (75 mg/m^2 on Day 1 of each 21-day
cycle), paclitaxel (80-100 mg/m^2 on Days 1, 8, and 15 of each 28-day
cycle), or irinotecan (80 mg/m^2 on Day 1 of each 14-day cycle).

About Esophageal Cancer

Esophageal cancer, a type of cancer
that is particularly difficult to treat, begins in the inner layer
(mucosa) of the esophagus and grows outward. There are two main types of
esophageal cancer: squamous cell carcinoma and adenocarcinoma. Globally,
esophageal cancer is the seventh most commonly diagnosed cancer. This
year, an estimated 17,290 adults in the United States will be diagnosed
with esophageal cancer, and 15,850 deaths from this disease will occur.
Worldwide, there are estimated to be over 572,000 new cases of
esophageal cancer and approximately 508,000 deaths resulting from this
disease in 2018 alone.

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 850 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

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

KEYTRUDA, as a single agent, is 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.

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
clinical trials in patients with multiple myeloma, the addition of
KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in
increased mortality. Treatment of these patients with a PD-1 or PD-L1
blocking antibody in this combination is not recommended outside of
controlled clinical trials.

Embryofetal Toxicity

Based on its mechanism of action,
KEYTRUDA can cause fetal harm when administered to a pregnant woman. If
used during pregnancy, or if the patient becomes pregnant during
treatment, apprise the patient of the potential hazard to a fetus.
Advise females of reproductive potential to use highly effective
contraception during treatment and for 4 months after the last dose of
KEYTRUDA.

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%).

Lactation

It is not known whether KEYTRUDA is excreted in
human milk. Because many drugs are excreted in human milk, instruct
women to discontinue nursing during treatment with KEYTRUDA and for 4
months after the final dose.

Pediatric Use

There is limited experience in pediatric
patients. In a study in 40 pediatric patients with advanced melanoma,
lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid
tumors, the safety profile was similar to that seen in adults treated
with KEYTRUDA. Toxicities that occurred at a higher rate (≥15%
difference) in these patients when compared to adults under 65 years of
age were fatigue (45%), vomiting (38%), abdominal pain (28%),
hypertransaminasemia (28%), and hyponatremia (18%).

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

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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