FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination with Carboplatin and Either Paclitaxel or Nab-Paclitaxel for the First-Line Treatment of Patients with Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)

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October 30, 2018 4:09 pm ET

Approval Based on Results of Phase 3 KEYNOTE-407 Trial, Which Demonstrated Superior Overall Survival with KEYTRUDA in Combination with Chemotherapy Compared to Chemotherapy Alone

First Anti-PD-1 Approved for First-Line Treatment of Squamous NSCLC Regardless of PD-L1 Expression

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with
carboplatin and either paclitaxel or nab-paclitaxel, for the first-line
treatment of patients with metastatic squamous non-small cell lung
cancer (NSCLC) based on results from the KEYNOTE-407 trial. In the
pivotal Phase 3 trial of patients regardless of tumor PD-L1 expression
status, KEYTRUDA in combination with chemotherapy (carboplatin and
either paclitaxel or nab-paclitaxel) significantly improved overall
survival (OS), reducing the risk of death by 36 percent compared to
chemotherapy alone (HR=0.64 [95% CI, 0.49, 0.85]; p=0.0017). This
approval marks the first time an anti-PD-1 regimen has been approved for
the first-line treatment of squamous NSCLC regardless of tumor PD-L1
expression status.

“Today’s approval expands our current lung cancer indications to include
combination treatment in patients with squamous cell carcinoma, a type
of lung cancer that is particularly difficult to treat,” said Dr. Roger
M. Perlmutter, president, Merck Research Laboratories. “Approval by the
FDA has the potential to mean that KEYTRUDA can be used to improve
survival for more patients with this debilitating disease.”

Immune-mediated adverse reactions, which may be severe or fatal, can
occur with KEYTRUDA, including pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis, severe skin reactions, solid organ
transplant rejection, and complications of allogeneic hematopoietic stem
cell transplantation (HSCT). Based on the severity of the adverse
reaction, KEYTRUDA should be withheld or discontinued and
corticosteroids administered if appropriate. KEYTRUDA can also cause
severe or life-threatening infusion-related reactions. Based on its
mechanism of action, KEYTRUDA can cause fetal harm when administered to
a pregnant woman. For more information, see “Selected Important Safety
Information” below.

“The results that support this approval from the KEYNOTE-407 trial
demonstrate the potential of KEYTRUDA in combination with chemotherapy
in patients with squamous non-small cell lung cancer, regardless of
PD-L1 expression,” said Dr. Balazs Halmos, director of the
multidisciplinary thoracic oncology program at the Montefiore Einstein
Center for Cancer Care and director of clinical cancer genomics at the
Albert Einstein College of Medicine. “With this important approval, more
patients will have the opportunity to benefit from immunotherapy.”

KEYTRUDA is the first anti-PD-1 approved in the first-line setting as
both combination and monotherapy in certain patients with metastatic
NSCLC (see KEYTRUDA indications below). With this approval, all
appropriate patients with metastatic squamous NSCLC and all appropriate
patients with metastatic nonsquamous NSCLC and no EGFR or ALK
genomic tumor aberrations are now eligible for a KEYTRUDA-based regimen
as their first-line treatment option.

Data Supporting the Approval

The approval was based on data from KEYNOTE-407, a randomized,
double-blind, multicenter, placebo-controlled study. The key eligibility
criteria for this study were metastatic squamous NSCLC, regardless of
tumor PD-L1 expression status, and no prior systemic treatment for
metastatic disease. Patients with autoimmune disease that required
systemic therapy within two years of treatment; a medical condition that
required immunosuppression; or who had received more than 30 Gy of
thoracic radiation within the prior 26 weeks were ineligible. Patients
were randomized to receive KEYTRUDA 200 mg and carboplatin every three
weeks for four cycles, plus paclitaxel every three weeks for four cycles
or nab-paclitaxel on Days 1, 8 and 15 of every three-week cycle for
four cycles, followed by KEYTRUDA 200 mg every three weeks; or placebo
and carboplatin every three weeks for four cycles, plus paclitaxel every
three weeks for four cycles or nab-paclitaxel on Days 1, 8 and 15 of
every three-week cycle for four cycles, followed by placebo every
three weeks.

Treatment with KEYTRUDA or placebo continued until progression of
disease, unacceptable toxicity, or a maximum of 24 months. Patients in
the placebo arm were offered KEYTRUDA as a single agent at the time of
disease progression.

Primary efficacy outcome measures were OS as well as progression-free
survival (PFS) and objective response rate (ORR) as assessed by blinded
independent central review (BICR) using RECIST v1.1, modified to follow
a maximum of 10 target lesions and a maximum of five target lesions per
organ. An additional efficacy outcome measure was duration of response.

In KEYNOTE-407, there was a statistically significant improvement in OS,
PFS and ORR in patients randomized to KEYTRUDA in combination with
carboplatin and either paclitaxel or nab-paclitaxel compared with
patients randomized to placebo with carboplatin and either paclitaxel or
nab-paclitaxel.


Safety and Efficacy Results in KEYNOTE-407

Endpoint	KEYTRUDA Carboplatin Paclitaxel/Nab-paclitaxel	Placebo Carboplatin Paclitaxel/Nab-paclitaxel
	n=278	n=281
OS
Number of events (%)	85 (31%)	120 (43%)
Median in months (95% CI)	15.9 (13.2, NE)	11.3 (9.5, 14.8)
Hazard ratio* (95% CI)	0.64 (0.49, 0.85)
p-Value^†	0.0017
PFS
Number of events (%)	152 (55%)	197 (70%)
Median in months (95% CI)	6.4 (6.2, 8.3)	4.8 (4.3, 5.7)
Hazard ratio* (95% CI)	0.56 (0.45, 0.70)
p-Value^†	<0.0001
	n=101	n=103
Overall Response Rate ^‡
Overall response rate (95% CI)	58% (48, 68)	35% (26, 45)
Difference (95% CI)	23.6% (9.9, 36.4)
p-Value^§	0.0008
Duration of Response ^‡
Median duration of response in months (range)	7.2 (2.4, 12.4+)	4.9 (2.0, 12.4+)
* Based on the stratified Cox proportional hazard model
† Based on a stratified log-rank test
‡ ORR primary analysis and DOR analysis were conducted with the first 204 patients enrolled.
§ Based on a stratified Miettinen-Nurminen test
NE = not estimable

In KEYNOTE-407, safety data are available for the first 203 patients who
received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy
(n=102). The safety of KEYTRUDA in combination with carboplatin and
either paclitaxel or nab-paclitaxel was investigated in 101 patients at
the first interim analysis of KEYNOTE-407. KEYTRUDA was discontinued for
adverse reactions in 15 percent of patients with no single type of
adverse reaction accounting for the majority. Adverse reactions leading
to interruption of KEYTRUDA occurred in 43 percent of patients; the most
common (≥2%) were thrombocytopenia (20%) and neutropenia (11%), anemia
(6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious
adverse reactions were febrile neutropenia (6%), pneumonia (6%), and
urinary tract infection (3%). The most common adverse reactions (≥20%)
with KEYTRUDA in combination with chemotherapy were fatigue/asthenia,
nausea, constipation, diarrhea, decreased appetite, rash, vomiting,
cough, dyspnea, pyrexia, alopecia, and peripheral neuropathy.

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 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.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.
Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA,
including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%)
pneumonitis, 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 48
(1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3
(1.1%), and 4 (<0.1%) colitis. 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 19
(0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.4%), and 4 (<0.1%) hepatitis. 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, 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.

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%).

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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 the Merck Access Program for KEYTRUDA

At Merck, we are committed to supporting accessibility to our cancer
medicines. Merck provides multiple programs to help ensure that
appropriate patients who are prescribed KEYTRUDA have access to our
anti-PD-1 therapy. The Merck Access Program provides reimbursement
support for patients receiving KEYTRUDA, including information to help
with out-of-pocket costs and co-pay assistance for eligible patients.
Merck also offers free product through our patient assistance program to
eligible patients, primarily the uninsured, who, without our assistance,
could not afford their medicine. More information is available by
calling 855-257-3932 or visiting
www.merckaccessprogram-keytruda.com
.

About Merck’s Patient Support Program for KEYTRUDA

Merck is committed to helping provide patients and their caregivers
support throughout their treatment with KEYTRUDA. The KEY+YOU Patient
Support Program provides a range of resources and services. For further
information and to sign up, patients and physicians may call 85-KEYTRUDA
(855-398-7832) or visit www.keytruda.com.

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
with us on Twitter,
Facebook,
Instagram,
YouTube
and LinkedIn.

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

.