Merck’s KEYTRUDA (pembrolizumab) Significantly Improved Overall Survival Compared to Standard of Care, as Monotherapy and in Combination with Chemotherapy, as First-Line Treatment for Patients with Recurrent or Metastatic Head and Neck Cancer

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October 22, 2018 9:30 am ET

Survival Benefit Observed with KEYTRUDA Monotherapy in Patients Whose Tumors Expressed PD-L1 with CPS≥20 and CPS≥1 and in Total Patient Population for KEYTRUDA in Combination with Chemotherapy

KEYTRUDA is the First Anti-PD-1 Therapy to Demonstrate a Survival Benefit as First-Line Therapy for Head and Neck Cancer that has Recurred or Metastasized

Results from Pivotal Phase 3 KEYNOTE-048 Trial Presented Today at the ESMO 2018 Congress during the Presidential Symposium

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced the first presentation of interim data from the pivotal
Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1
therapy, as both monotherapy and in combination with chemotherapy, for
the first-line treatment of recurrent or metastatic head and neck
squamous cell carcinoma (HNSCC). These interim results are being
presented today during the Presidential Symposium at the ESMO 2018
Congress (Abstract # LBA8_PR) and are included in the official Press
Program.

Interim data from KEYNOTE-048 showed KEYTRUDA monotherapy improved
overall survival (OS), a primary endpoint of the study, by 39 percent
(HR 0.61 [95% CI, 0.45-0.83]; p=0.0007) in patients whose tumors
expressed PD-L1 with Combined Positive Score (CPS) ≥20, and by 22
percent (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086) in patients with CPS≥1,
compared to the EXTREME regimen (cetuximab with carboplatin or cisplatin
plus 5-fluorouracil (5-FU), the current standard of care. In addition,
KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus
5-FU) (KEYTRUDA combination) demonstrated improved OS compared to the
EXTREME regimen by 23 percent (HR 0.77 [95% CI, 0.63-0.93]; p=0.0034),
regardless of PD-L1 expression. At the final analysis, superiority for
OS will be evaluated for KEYTRUDA monotherapy in the total population
and KEYTRUDA combination in patients whose tumors express PD-L1 at
CPS≥20 and CPS≥1; at this interim analysis, based upon the prespecified
testing algorithm, non-inferiority for KEYTRUDA monotherapy in the total
population was demonstrated and statistical significance was not
achieved for the KEYTRUDA combination in the subset of patients whose
tumors expressed PD-L1 at CPS ≥20 or ≥1. Additionally, at this time
point there was no difference in progression-free-survival (PFS), a dual
primary endpoint of the study, in any of the groups studied. There were
no new safety concerns identified with the use of KEYTRUDA in
KEYNOTE-048.

“In this study, KEYTRUDA showed the potential to significantly prolong
survival when used as first-line therapy for patients whose head and
neck cancer had recurred or spread,” said Dr. Barbara Burtness, lead
investigator for KEYNOTE-048, professor of medicine at Yale School of
Medicine and co-director, Development Therapeutics Research Program,
Yale Cancer Center. ”This is a devastating cancer when it recurs, and
there has not been any advance in first-line treatment for over a
decade. It is thrilling to see these new data, which have the potential
to alter the standard of care in the first-line treatment of head and
neck cancer.”

“KEYTRUDA is the first anti-PD-1 therapy to show superior overall
survival as first-line treatment compared to the EXTREME regimen, the
current standard of care in patients with recurrent or metastatic head
and neck cancer,” said Dr. Roy Baynes, senior vice president and head of
Global Clinical Development, chief medical officer, Merck Research
Laboratories. “Recurrent or metastatic head and neck cancer is a very
challenging disease. Merck would like to thank the patients and
investigators for participating in this important study, which is
helping to advance our understanding of the potential for KEYTRUDA and
PD-1 inhibition in the first-line setting.”

KEYTRUDA is currently approved in 61 countries for the treatment of
second-line recurrent or metastatic HNSCC, including the U.S. and
Europe. Merck plans to file a supplemental Biologics License Application
(sBLA) with the U.S. Food and Drug Administration (FDA) for a first-line
indication based on KEYNOTE-048 data and will include data from the
Phase 3 KEYNOTE-040 trial as supportive data. Based on these results,
Merck has withdrawn the sBLA for KEYNOTE-040 for KEYTRUDA as a
second-line treatment in patients with recurrent or metastatic HNSCC,
which was previously assigned a Prescription Drug User Fee Act (PDUFA)
or target action date of Dec. 28, 2018. The results from KEYNOTE-048
will also be submitted to regulatory authorities worldwide.

Study Design and Additional Data from KEYNOTE-048 (Abstract # LBA8_PR)

KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov,
NCT02358031), evaluated KEYTRUDA monotherapy or KEYTRUDA combination,
compared with the EXTREME regimen, as first-line treatment in 882
patients with recurrent or metastatic HSNCC. The dual primary endpoints
were OS and PFS. The secondary endpoints were PFS (at 6 months and 12
months), objective response rate (ORR) and time to deterioration in
Quality of Life Global Health Status/Quality of Life Scales of the
European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire and Safety. Duration of response (DOR) was
evaluated as part of a pre-specified exploratory analysis. The primary
and secondary endpoints, as well as exploratory DOR analysis, were
evaluated in patients whose tumors expressed PD-L1 with CPS ≥20 and CPS
≥1, and in the total population, regardless of PD-L1 expression, based
on a fixed sequential testing strategy. At the time of the analysis, the
median follow-up was 11.7 months for KEYTRUDA monotherapy, 13.0 months
for KEYTRUDA combination and 10.7 months for the EXTREME regimen,
respectively.

In the first comparison group, OS in the CPS ≥20 population was
significantly longer with KEYTRUDA monotherapy (14.9 months) (n=133)
compared to the EXTREME regimen (10.7 months) (n=122) (HR 0.61 [95% CI,
0.45-0.83]; p=0.0007). There was no difference in PFS between the study
arms (HR 0.99 [95% CI, 0.75-1.29]; p=0.5). ORR was 23.3 percent for
KEYTRUDA monotherapy and 36.1 percent for the EXTREME regimen,
respectively. The median DOR was substantially longer with KEYTRUDA
monotherapy (20.9 months) compared to the EXTREME regimen (4.2 months).

Similarly, OS in the CPS ≥1 population was significantly longer with
KEYTRUDA monotherapy (12.3 months) (n=257) compared to the EXTREME
regimen (10.3 months) (n=255) (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086).
There was no difference in PFS between the study arms (HR 1.16 [95% CI,
0.96-1.39]). ORR was 19.1 percent for KEYTRUDA monotherapy and 34.9
percent for the EXTREME regimen, respectively. The median DOR was
substantially longer with KEYTRUDA (20.9 months) compared to the EXTREME
regimen (4.5 months).

In the second comparison group, OS in the total population was
significantly longer with the KEYTRUDA combination (13.0 months) (n=281)
compared to the EXTREME regimen (10.7 months) (n=278) (HR 0.77 [95% CI,
0.63-0.93]; p=0.0034). There was no difference in PFS between the study
arms (HR 0.92; 95% CI, 0.77-1.10). ORR was 35.6 percent for the KEYTRUDA
combination and 36.3 percent for the EXTREME regimen, respectively. The
median DOR was longer with KEYTRUDA combination (6.7 months) compared to
the EXTREME regimen (4.3 months).

There were no new safety concerns identified with the use of KEYTRUDA in
KEYNOTE-048. Grade 3-5 treatment-related adverse events (TRAEs) occurred
in 16.7 percent, 71.0 percent and 69.0 percent (n=198/287) of patients
in the KEYTRUDA monotherapy, KEYTRUDA combination and the EXTREME
regimen arms, respectively. TRAEs resulting in discontinuation occurred
in 4.7 percent, 22.8 percent and 19.9 percent of patients in the
KEYTRUDA monotherapy, KEYTRUDA combination and the EXTREME regimen arms,
respectively. There were no TRAEs observed with an incidence of ≥15% in
the KEYTRUDA monotherapy arm. The most common TRAEs (occurring in ≥15%
of patients) in the KEYTRUDA combination arm included anemia (48.2%),
nausea (44.9%), neutropenia (33.0%), fatigue (30.4%), mucosal
inflammation (27.9%), thrombocytopenia (27.2%), vomiting (27.2%),
stomatitis (24.3%), decreased appetite (22.5%), platelet count decreased
(18.5%), diarrhea (17.8%) and neutrophil count decreased (16.7%).

Immune-mediated adverse events in patients receiving KEYTRUDA
monotherapy or combination therapy were hypothyroidism (18.0% and 15.2%,
respectively), pneumonitis (6.0% and 5.4%, respectively),
hyperthyroidism (2.7% and 4.7%, respectively), severe skin reactions
(2.7% and 0.7%, respectively), infusion reactions (1.3% and 2.2%,
respectively), colitis (1.0% and 2.5%, respectively), nephritis (0.7% in
both arms), pancreatitis (0.7% and 0.4%, respectively), hypophysitis
(0.3% and 0.4%, respectively); hepatitis (0.7% monotherapy only);
myocarditis and thyroiditis (0.4% each, combination only); and adrenal
insufficiency, encephalitis and uveitis (0.3% each, monotherapy only).
Treatment-related deaths occurred in 3 patients in the KEYTRUDA
monotherapy arm [auto-inflammatory disease, disseminated intravascular
coagulation, and pneumonitis (n=1 each)]; 10 patients in the KEYTRUDA
combination arm [septic shock (n=5), cerebral ischemia, hemorrhage,
interstitial lung disease, sepsis, and tumor hemorrhage (n=1 each)]; and
8 patients in the EXTREME regimen arm [pneumonia (n=3), sepsis (n=2),
and hypoxia, osteomyelitis, and pulmonary artery thrombosis (n=1 each)].

Additional Information About KEYNOTE-048

KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HSNCC who
were randomized to one of three regimens as first-line therapy, as
follows:

KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for
up to 24 months (n=301); or
KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100
mg/m² IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000
mg/m²/day IV continuous from Day 1-4 Q3W (maximum six
cycles), followed by additional KEYTRUDA monotherapy maintenance
therapy until progression of disease, toxicity or until the patient
had received a maximum of 24 months total treatment (n=281); or
EXTREME regimen including cetuximab at a loading dose (400 mg/m²
IV) followed by weekly doses (250 mg/m² IV) in combination
with cisplatin (100 mg/m² IV Q3W) or carboplatin (AUC 5 IV
Q3W) plus 5-FU (1000 mg/m²/day IV) continuous from Day 1-4
Q3W (maximum six cycles), followed by additional cetuximab monotherapy
maintenance therapy until progression of disease or toxicity (n=300).

About Head and Neck Cancer

Head and neck cancer describes a number of different tumors that develop
in or around the throat, larynx, nose, sinuses and mouth. Most head and
neck cancers are squamous cell carcinomas that begin in the flat,
squamous cells that make up the thin surface layer of the structures in
the head and neck. The leading modifiable risk factors for head and neck
cancer include tobacco and heavy alcohol use. Other risk factors include
infection with certain types of HPV, also called human papillomaviruses.
Worldwide, an estimated 835,000 new head and neck cancer cases will be
diagnosed in 2018, and an estimated 431,000 people will die from the
disease this year. In the U.S., there were an estimated 63,000 new cases
diagnosed in 2017.

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 NSCLC, with no EGFR or ALK genomic tumor aberrations.

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 also indicated for the treatment of
patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as
determined by an FDA-approved test, with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA.

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

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA
should be administered prior to chemotherapy when given on the same day.
See also the Prescribing Information for pemetrexed and carboplatin or
cisplatin, 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 three or more prior lines of therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. In adults with cHL, KEYTRUDA is administered at a
fixed dose of 200 mg every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with cHL, KEYTRUDA is administered at
a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.

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 also 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.

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 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 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-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, 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%).

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%).

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

For more than a century, Merck, a leading global biopharmaceutical
company known as MSD outside of the United States and Canada, has been
inventing for life, bringing forward medicines and vaccines for many of
the world’s most challenging diseases. Through our prescription
medicines, vaccines, biologic therapies and animal health products, we
work with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to health care through far-reaching policies, programs
and partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world – including cancer,
cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect
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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
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 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

.