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April 16, 2018 8:30 am ET

KEYTRUDA Combination Improved Overall Survival in Patients Regardless of PD-L1 Expression, Including Patients Who Tested Negative for PD-L1

Results Presented Today at AACR 2018 and Published in The New England Journal of Medicine Also Show Significant Improvement in Progression-Free Survival, with Risk of Progression or Death Reduced by Nearly Half

Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced results from KEYNOTE-189, a pivotal Phase 3 trial
evaluating KEYTRUDA
^®
, Merck’s anti-PD-1 therapy, in
combination with pemetrexed (ALIMTA^®) and cisplatin or
carboplatin for the first-line treatment of metastatic nonsquamous
non-small cell lung cancer (NSCLC). Findings showed that the
KEYTRUDA-pemetrexed-platinum chemotherapy combination significantly
improved overall survival (OS), reducing the risk of death by half
compared with chemotherapy alone (HR=0.49 [95% CI, 0.38-0.64];
p<0.00001). In pre-specified exploratory analyses, an OS benefit was
observed regardless of PD-L1 expression in the three PD-L1 categories
that were evaluated, including: patients whose tumors were negative for
PD-L1 (HR=0.59 [95% CI, 0.38-0.92]); patients whose tumors had PD-L1
tumor proportion scores (TPS) of 1-49 percent (HR=0.55 [95% CI,
0.34-0.90]); and patients who had a TPS of greater than or equal to 50
percent (HR=0.42 [95% CI, 0.26-0.68]). The addition of KEYTRUDA to
pemetrexed plus platinum chemotherapy also achieved a significant
improvement in progression-free survival (PFS), with a reduction in the
risk of progression or death of nearly half for patients in the KEYTRUDA
combination arm, compared with chemotherapy alone (HR=0.52 [95% CI,
0.43-0.64]; p<0.00001). A PFS improvement in the KEYTRUDA combination
group was observed in patients whose tumors were negative for PD-L1
(HR=0.75 [95% CI, 0.53-1.05]); patients with a TPS of 1-49 percent
(HR=0.55 [95% CI, 0.37-0.81]); and patients with a TPS greater than or
equal to 50 percent (HR=0.36 [95% CI, 0.25-0.52]). These results are
being presented today in a plenary session at the American Association
for Cancer Research (AACR) Annual Meeting 2018 (Abstract #CT075), with
simultaneous publication in The New England Journal of Medicine.

“In this trial, KEYTRUDA in combination with pemetrexed and platinum
chemotherapy, compared with chemotherapy alone, prolonged overall
survival and progression-free survival in patients with advanced
nonsquamous non-small cell lung cancer regardless of PD-L1 expression,”
said Dr. Leena Gandhi, director of thoracic medical oncology at NYU
Langone’s Perlmutter Cancer Center and lead author of The New England
Journal of Medicine paper. “There is good scientific rationale for
combining KEYTRUDA with pemetrexed and platinum chemotherapy, and these
clinical data now suggest this combination as a new standard of care for
the first-line treatment of these nonsquamous non-small cell lung cancer
patients.”

“Our goal is to extend the lives of patients with lung cancer, and the
unambiguous survival findings from KEYNOTE-189 showing the risk of death
was reduced by half in the KEYTRUDA arm are important not only for
patients but also for the medical community,” said Dr. Roger M.
Perlmutter, president, Merck Research Laboratories. “The results of this
trial have the potential to change the treatment paradigm for patients
with nonsquamous non-small cell lung cancer in the first-line setting,
including patients whose tumors are either PD-L1 negative or are
untested.”

KEYTRUDA is the first immunotherapy to significantly extend survival of
patients with nonsquamous NSCLC in combination with chemotherapy as a
first-line treatment. KEYNOTE-189 is the confirmatory trial for
KEYNOTE-021 (Cohort G), a Phase 2 study that made KEYTRUDA the only
FDA-approved anti-PD-1 therapy in combination with chemotherapy
(pemetrexed plus carboplatin) for the first-line treatment of patients
with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Merck
is working to submit data from KEYNOTE-189 to regulatory agencies in the
United States and around the world.

Merck has an extensive clinical development program in lung cancer and
is advancing multiple registration-enabling studies with KEYTRUDA in
combination with other treatments and as monotherapy. The program, which
is comprised of nearly 9,000 patients across 15 clinical studies, is
evaluating KEYTRUDA across multiple settings and stages of the disease.

“The reality is, there remains a significant need for treatment options
for patients with lung cancer. At the Bonnie J. Addario Lung Cancer
Foundation (ALCF), we are devoted exclusively to eradicating lung cancer
through research, early detection, education and treatment. And, the
survival benefit achieved by the KEYTRUDA combination in the KEYNOTE-189
study represents a meaningful advance and may offer hope for patients
newly diagnosed with one of the most common and deadly cancers,” said
Bonnie J. Addario, a 14-year lung cancer survivor and ALCF founder.

Additional Data and Safety Information from KEYNOTE-189 (Abstract
#CT075)

KEYNOTE-189, a randomized, double-blind,
placebo-controlled, Phase 3 study, evaluated KEYTRUDA in combination
with pemetrexed and cisplatin or carboplatin, compared with pemetrexed
and cisplatin or carboplatin alone, in 616 untreated patients with
metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients
had no sensitizing EGFR or ALK genomic tumor aberrations,
and had not previously received systemic therapy for advanced disease.
The dual primary endpoints were OS and PFS; secondary endpoints include
overall response rate (ORR) and duration of response (DOR).

With a median follow-up of 10.5 months (range, 0.2-20.4), KEYTRUDA in
combination with pemetrexed and a platinum chemotherapy demonstrated
superior improvements in OS, with a 51 percent reduction in the risk of
death, compared with pemetrexed plus platinum chemotherapy alone
(HR=0.49 [95% CI, 0.38-0.64]; p<0.00001). This finding includes the 50
percent of patients randomized to the chemotherapy alone group who
discontinued all study therapy (n=170) and went on to receive subsequent
anti-PD-1 or PD-L1 therapy, including 67 patients who received KEYTRUDA
monotherapy as part of study crossover. Median OS was not reached in the
KEYTRUDA combination group (95% CI, not estimable) and was 11.3 months
in the chemotherapy alone group (95% CI, 8.7-15.1). In the study, 69.2
percent of patients were estimated to be alive at 12 months in the
KEYTRUDA treatment group (95% CI, 64.1-73.8%) compared with 49.4 percent
in the chemotherapy alone group (95% CI, 42.1-56.2%).

In KEYNOTE-189 there was also a significant improvement in PFS for
KEYTRUDA in combination with pemetrexed and platinum chemotherapy with a
48 percent reduction in the risk of progression or death compared with
pemetrexed plus platinum chemotherapy alone (HR=0.52 [95% CI,
0.43-0.64]; p<0.00001). The median PFS was 8.8 months for the KEYTRUDA
combination (95% CI, 7.6-9.2) compared with 4.9 months for chemotherapy
alone (95% CI, 4.7-5.5). The percentage of patients who were alive with
no progression of disease at 12 months was 34.1 percent in the KEYTRUDA
combination group (95% CI, 28.8-39.5%), which was nearly double the
percentage of the pemetrexed plus platinum chemotherapy group (17.3
percent [95% CI, 12.0-23.5%]). In addition, improvements in OS and PFS
were observed in other patient subgroups evaluated, including age, sex,
EGOG performance-status score, smoking status, brain metastases at
baseline and type of platinum chemotherapy prescribed (carboplatin or
cisplatin).

In the study, KEYTRUDA plus pemetrexed and a platinum chemotherapy also
showed an ORR that was more than double the ORR of chemotherapy alone
(47.6 percent [95% CI, 42.6-52.5%] compared to 18.9 percent [95% CI,
13.8-25.0%], respectively, p<0.00001). Among patients in the KEYTRUDA
arm, the median duration of response was 11.2 months (range, 1.1+ to
18.0+ months) compared with 7.8 months in the chemotherapy alone group
(range, 2.1+ to 16.4+ months). The improvement in response rate occurred
in all PD-L1 patient subgroups.

The safety of KEYTRUDA was consistent with what has been seen in
previous trials among patients with metastatic NSCLC. Grade 3-5 adverse
events from any cause occurred in 67.2 percent of patients in the
KEYTRUDA plus pemetrexed and platinum chemotherapy group and 65.8
percent in the chemotherapy alone arm. Adverse events of any grade and
from any cause with an incidence of 15 percent or more in the KEYTRUDA
group were nausea (55.6%), anemia (46.2%), fatigue (40.7%), constipation
(34.8%), diarrhea (30.9%), decreased appetite (28.1%), neutropenia
(27.2%), vomiting (24.2%), cough (21.5%), dyspnea (21.2%), asthenia
(20.5%), rash (20.2%), pyrexia (19.5%), edema peripheral (19.3%),
thrombocytopenia (18.0%) and increased lacrimation (17.0%). The most
common immune-mediated adverse events of any grade in patients receiving
KEYTRUDA plus pemetrexed and platinum chemotherapy were hypothyroidism
(6.7%), pneumonitis (4.4%), hyperthyroidism (4.0%), infusion reactions
(2.5%), colitis (2.2%), severe skin toxicity (2.0%), nephritis (1.7%)
and hepatitis (1.2%). There were three treatment-related deaths from
pneumonitis in the KEYTRUDA plus pemetrexed and platinum chemotherapy
group.

About KEYNOTE-189

KEYNOTE-189 (ClinicalTrials.gov,
NCT02578680) enrolled 616 patients who were randomized 2:1 to one of two
treatment groups, and were treated until disease progression,
unacceptable toxicity, physician decision or consent withdrawal, as
follows:

• KEYTRUDA (200 mg fixed dose every three weeks) plus pemetrexed (500
  mg/m²) (with vitamin supplementation) plus cisplatin (75
  mg/m²) or carboplatin AUC 5 mg/mL/min on day 1 every three
  weeks (Q3W) for four cycles, followed by KEYTRUDA 200 mg plus
  pemetrexed (500 mg/m²) Q3W; or
• Saline placebo plus pemetrexed (500 mg/m²) (with vitamin
  supplementation) plus cisplatin (75 mg/m²) or carboplatin
  AUC 5 mg/mL/min on day 1 every three weeks (Q3W) for four cycles,
  followed by placebo plus pemetrexed (500 mg/m²) Q3W.

Patients on the control arm who experienced disease progression,
verified by central independent review, were permitted to undergo
treatment assignment unblinding and crossover to receive open-label
KEYTRUDA. The KEYNOTE-189 study was conducted in collaboration with Eli
Lilly and Company, the makers of pemetrexed (ALIMTA).

About Lung Cancer

Lung cancer, which forms in the tissues of
the lungs, usually within cells lining the air passages, is the leading
cause of cancer death worldwide. Each year, more people die of lung
cancer than die of colon, breast and prostate cancers combined. The two
main types of lung cancer are non-small cell and small cell. NSCLC is
the most common type of lung cancer, accounting for about 85 percent of
all cases. The five-year survival rate for patients diagnosed in the
United States with any stage of lung cancer is estimated to be 18
percent.

Merck Investor Webcast

Merck will hold a live investor audio
webcast in conjunction with the AACR 2018 Annual Meeting on Monday,
April 16 at 6:45 p.m. CDT (7:45 p.m. EDT). Those interested in
participating can register and join here.

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, which currently involves more than 700 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, 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.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated
for the first-line treatment of patients with metastatic nonsquamous
NSCLC. This indication is approved under accelerated approval based on
tumor response rate and progression-free survival. Continued approval
for this indication may be contingent upon verification and description
of clinical benefit in the confirmatory trials.

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.

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.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment
of patients with locally advanced or metastatic urothelial carcinoma who
are not eligible for cisplatin-containing chemotherapy. 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 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 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

^®


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.

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.

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.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of
2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%),
and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of
hypophysitis (including hypopituitarism and adrenal insufficiency).
Administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for
Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%)
of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3
(0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799
patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%)
hypothyroidism. The incidence of new or worsening hypothyroidism was
higher in patients with HNSCC, occurring in 28 (15%) of 192 patients
with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis
occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including
Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid
function (at the start of treatment, periodically during treatment, and
as indicated based on clinical evaluation) and for clinical signs and
symptoms of thyroid disorders. Administer replacement hormones for
hypothyroidism and manage hyperthyroidism with thionamides and
beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade
3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients.
Monitor patients for hyperglycemia or other signs and symptoms of
diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA
and administer antihyperglycemics in patients with severe hyperglycemia.

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

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.

KEYTRUDA can cause other clinically important immune-mediated adverse
reactions. These immune-mediated reactions may occur in any organ
system. 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, and partial seizures
arising in a patient with inflammatory foci in brain parenchyma. In
addition, myelitis and myocarditis were reported in other clinical
trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use
of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection
in solid organ transplant recipients. Consider the benefit of treatment
with KEYTRUDA vs the risk of possible organ rejection in these patients.

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

Immune-mediated complications, including fatal events, occurred in
patients who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients
with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA
on any trial, 6 patients (26%) developed graft-versus-host disease
(GVHD), one of which was fatal, and 2 patients (9%) developed severe
hepatic veno-occlusive disease (VOD) after reduced-intensity
conditioning, one of which was fatal. 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.

These complications may occur despite intervening therapy between PD-1
blockade and allogeneic HSCT. Follow patients closely for early evidence
of transplant-related complications such as hyperacute GVHD, severe
(Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic
VOD, and other immune-mediated adverse reactions, and intervene promptly.

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.

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.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9%
of 555 patients with advanced melanoma; adverse reactions leading to
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%). Adverse reactions leading to interruption of
KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea
(2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab
were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs
23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are
listed for ipilimumab only for those adverse reactions that occurred at
the same or lower rate than with KEYTRUDA.

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%). Adverse reactions leading to interruption of
KEYTRUDA occurred in 23% of patients; the most common (≥1%) were
diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation
(1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common
adverse reactions (occurring in at least 20% of patients and at a higher
incidence than with docetaxel) were decreased appetite (25% vs 23%),
dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with
carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC,
KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse
reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney
injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA
occurred in 39% of patients; the most common (≥2%) were fatigue (8%),
neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and
pneumonitis (3.4%). The most common adverse reactions (≥20%) with
KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea
(68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting
(39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased
appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%),
dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%),
peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs
3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia
(15% vs 24%). This study was not designed to demonstrate a statistically
significant difference in adverse reaction rates for KEYTRUDA as
compared to carbo/pem alone for any specified adverse reaction.

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 (reported in at least 20% of patients) 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 (10% all Grades; 2.1% Grades 3 or 4) and new or worsening
hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5%
of 210 patients with cHL, and treatment was interrupted due to adverse
reactions in 26% of patients. Fifteen percent (15%) of patients had an
adverse reaction requiring systemic corticosteroid therapy. Serious
adverse reactions occurred in 16% of patients. The most frequent serious
adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia,
dyspnea, GVHD, and herpes zoster. Two patients died from causes other
than disease progression; one from GVHD after subsequent allogeneic HSCT
and one from septic shock. The most common adverse reactions (occurring
in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in
11% of 370 patients with locally advanced or metastatic urothelial
carcinoma. The most common adverse reactions (in ≥20% of patients) were
fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%),
constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients
(5%) died from causes other than disease progression. Five patients
(1.4%) who were treated with KEYTRUDA experienced sepsis which led to
death, and 3 patients (0.8%) experienced pneumonia which led to death.
Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of
patients; the most common (≥1%) were liver enzyme increase, diarrhea,
urinary tract infection, acute kidney injury, fatigue, joint pain, and
pneumonia. Serious adverse reactions occurred in 42% of patients, the
most frequent (≥2%) of which were urinary tract infection, hematuria,
acute kidney injury, pneumonia, and urosepsis.

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%). Adverse reactions
leading to interruption of KEYTRUDA occurred in 20% of patients; the
most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%),
and colitis (1.1%). The most common adverse reactions (≥20%) in patients
who received KEYTRUDA vs those who received chemotherapy were fatigue
(38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%),
decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs
13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients, the most frequent (≥2%) of which were urinary tract infection,
pneumonia, anemia, and pneumonitis.

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.

There is limited experience in pediatric patients. In a study, 40
pediatric patients (16 children aged 2 years to younger than 12 years
and 24 adolescents aged 12 years to 18 years) with advanced melanoma,
lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid
tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients
received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34
patients (85%) receiving KEYTRUDA for 2 doses or more. The safety
profile in these pediatric patients 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, helping people fight cancer is our
passion and supporting accessibility to our cancer medicines is our
commitment. Our focus is on pursuing research in immuno-oncology and we
are accelerating every step in the journey – from lab to clinic – to
potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the fastest-growing development
programs in the industry. We are currently executing an expansive
research program evaluating our anti-PD-1 therapy across more than 30
tumor types. We also continue to strengthen our immuno-oncology
portfolio through strategic acquisitions and are prioritizing the
development of several promising immunotherapeutic 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 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

https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf


and

Patient Information/Medication Guide for KEYTRUDA at

https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf

.

ALIMTA^® is a registered trademark of Eli Lilly and Company.

Merck
Media:
Pamela Eisele, 267-305-3558
or
Kristen Drake, 908-334-4688
or
Investors:
Teri Loxam, 908-740-1986
or
Michael DeCarbo, 908-740-1807