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April 19, 2015 7:30 am ET

…in a Phase 3 Study of Patients with Advanced Melanoma

Data from KEYNOTE-006 Study Presented at AACR Annual Meeting and Published in the New England Journal of Medicine

Merck Plans to Submit sBLA for First-Line Indication in Advanced Melanoma in Mid-2015

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced results from the randomized, pivotal Phase 3 study,
KEYNOTE-006, in the treatment of unresectable advanced melanoma. In the
study, KEYTRUDA^® (pembrolizumab) was statistically superior
to ipilimumab for progression-free survival (PFS), overall survival
(OS), and overall response rate (ORR). On March 24, 2015, Merck
announced that KEYNOTE-006 would be stopped early based on these data (link).
The results will be presented today at the American Association for
Cancer Research (AACR) Annual Meeting by Dr. Antoni Ribas of Jonsson
Comprehensive Cancer Center, University of California, Los Angeles
(abstract # CT101), included in the AACR press program, and were also
published today in the New England Journal of Medicine.

“Improving survival is the ultimate objective in treating patients with
cancer. In this important study in advanced melanoma, KEYTRUDA was
statistically superior to ipilimumab for progression-free survival and
overall survival, and also demonstrated a lower frequency of severe
adverse events.” said Dr. Caroline Robert, head of dermatology at
Gustave Roussy, Villejuif and Paris-Sud University Cancer Campus, Grand
Paris and lead author of the New England Journal of Medicine
publication.

In mid-2015, Merck plans to submit a supplemental Biologics License
Application (sBLA) for KEYTRUDA based on KEYNOTE-006 for the first-line
treatment of advanced melanoma. Merck recently submitted data from
KEYNOTE-002 in ipilimumab-refractory advanced melanoma as part of a
supplemental application. KEYTRUDA was the first anti-PD-1 therapy
approved in the United States and is currently indicated in the United
States for the treatment of patients with unresectable or metastatic
melanoma and disease progression following ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor. Please see below for complete
indication and selected safety information for KEYTRUDA.

“Our goal with the KEYTRUDA development program is to help improve
long-term disease control and survival for people suffering from a wide
range of cancers,” said Dr. Roger Perlmutter, president, Merck Research
Laboratories. “The KEYNOTE-006 study compared two immunotherapies that
target distinct immune checkpoint pathways, PD-1 and CTLA-4. In this
study, our anti-PD-1 antibody, KEYTRUDA, improved overall survival by
more than 30 percent compared to ipilimumab, an anti-CTLA-4 antibody, in
the treatment of advanced melanoma. We look forward to filing these data
with the FDA and health authorities around the world.”

KEYNOTE-006 Results in the Front-Line Treatment of Advanced Melanoma

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study
(ClinicalTrials.gov, NCT01866319) of 834 patients from 16 countries with
unresectable stage III or IV advanced melanoma with no more than one
prior systemic therapy. Patients received KEYTRUDA 10 mg/kg every two
weeks (n=279), KEYTRUDA 10 mg/kg every three weeks (n=277), or four
cycles of ipilimumab 3 mg/kg every three weeks (n=278). The primary
endpoints were PFS and OS; secondary endpoints were ORR, duration of
response, and safety. Tumor response was assessed at week 12, then every
six weeks thereafter by independent central review per RECIST 1.1. This
first presentation of data from KEYNOTE-006 is based on interim analyses
conducted for PFS with a data cut-off of September 3, 2014 (median
follow-up, 7.9 months) and for OS with a data cut off of March 3, 2015
(median follow-up, 13.8 months).

Data Showed KEYTRUDA was Statistically Superior to Ipilimumab for
PFS, OS and ORR

The median PFS for KEYTRUDA was 5.5 months (2-week group) and 4.1 months
(3-week group) compared to 2.8 months for ipilimumab (HR 0.58, P<0.00001
for the KEYTRUDA groups vs. ipilimumab, 95% CI, 0.46-0.72 for 2-week
group and 0.47-0.72 for 3-week group, respectively). The estimated
6-month PFS rates for the KEYTRUDA and ipilimumab arms were 47.3
percent, 46.4 percent and 26.5 percent, respectively. One-year OS for
KEYTRUDA was 74.1 percent (2-week group) and 68.4 percent (3-week group)
compared to 58.2 percent for ipilimumab (HR 0.63 [95% CI, 0.47-0.83, P=0.00052]
for the 2-week group and HR 0.69 [95% CI, 0.52-0.90, P=0.00358]
for the 3-week group). At the time of analysis, median overall survival
was not reached in any treatment group.

ORR for KEYTRUDA was 33.7 percent (2-week group) and 32.9 percent
(3-week group) compared to 11.9 percent for ipilimumab (P=0.00013
for 2-week group; P=0.00002 for 3-week group); complete response
rates were 5.0 percent, 6.1 percent, and 1.4 percent, respectively.
Responses were ongoing in 89.4 percent (2-week group) and 96.7 percent
(3-week group) of KEYTRUDA-treated patients and in 87.9 percent of
ipilimumab-treated patients. Median duration of response was not reached
for KEYTRUDA 3-week group (42+ to 246+) and ipilimumab (33+ to 239+).

The efficacy and safety profiles were similar between the two KEYTRUDA
schedules evaluated in the study. Two previous studies, KEYNOTE-001 and
KEYNOTE-002, demonstrated that the efficacy and safety were similar
among the KEYTRUDA doses and schedules evaluated; 10 mg/kg every two
weeks, 10 mg/kg every three weeks, and 2 mg/kg every three weeks (the
currently approved dose in the U.S.).

Safety Findings from KEYNOTE-006

The safety profile of KEYTRUDA in this study was generally consistent
with the safety described in the prescribing information. The most
common treatment-related adverse events of any grade occurring in the
KEYTRUDA groups were fatigue, diarrhea, rash, and pruritus. For
ipilimumab, the most frequent treatment-related adverse events were
pruritus, diarrhea, fatigue, and rash. Grade 3 to 4 treatment-related
adverse events occurred in 13.3 percent (2-week group) and 10.1 percent
(3-week group) of patients treated with KEYTRUDA and in 19.9 percent for
ipilimumab. Discontinuation due to treatment-related adverse events was
less frequent with KEYTRUDA (2-week group and 3-week group) than with
ipilimumab (4.0%, 6.9%, and 9.4%, respectively). One death in the
ipilimumab group was attributed to study treatment.

Treatment-related adverse events of an autoimmune or immune-related
nature most frequently observed with KEYTRUDA (2-week group and 3-week
group) were hypothyroidism (10.1% and 8.7%) and hyperthyroidism (6.5%
and 3.2%). With ipilimumab, colitis occurred in 8.2 percent of patients.
Grade 3 to 4 inflammatory or immune-mediated treatment events reported
in more than 1 percent of KEYTRUDA-treated patients (2-week group and
3-week group) were colitis (1.4% and 2.5%) and hepatitis (1.1% and
1.8%), and in ipilimumab-treated patients were colitis (7.0%) and
hypophysitis (1.6%).

About KEYTRUDA^® (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks
the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By
binding to the PD-1 receptor and blocking the interaction with the
receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition
of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg
administered as an intravenous infusion over 30 minutes every three
weeks for the treatment of patients with unresectable or metastatic
melanoma and disease progression following ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor. This indication is approved under
accelerated approval based on tumor response rate and durability of
response. An improvement in survival or disease-related symptoms has not
yet been established. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in the
confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program
for KEYTRUDA with more than 85 clinical trials – across more than 30
tumor types and over 14,000 patients – both as a monotherapy and in
combination with other therapies.

Selected Important Safety Information for KEYTRUDA^®

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma
receiving KEYTRUDA (the approved indication in the United States),
including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients,
respectively. 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
pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411
patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients
respectively, receiving KEYTRUDA. 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.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411
patients, including a Grade 4 case in 1 (0.2%) patient, receiving
KEYTRUDA. 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.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2
case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving
KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer
corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA
for Grade 2; withhold or discontinue for Grade 3; and permanently
discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting
of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of
interstitial nephritis with renal failure (0.5%), one Grade 3 and one
Grade 4. 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.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2
or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving
KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients,
including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA.
Thyroid disorders can occur at any time during treatment. 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 corticosteroids for Grade 3 or greater hyperthyroidism.
Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for
Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with
replacement therapy without treatment interruption and without
corticosteroids.

Other clinically important immune-mediated adverse reactions can occur.
The following clinically significant, immune-mediated adverse reactions
occurred in less than 1% of patients treated with KEYTRUDA: exfoliative
dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic
anemia, partial seizures arising in a patient with inflammatory foci in
brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic
neuritis, and rhabdomyolysis.

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 of the adverse reaction to Grade 1 or
less, initiate corticosteroid taper and continue to taper over at least
1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or
less. Permanently discontinue KEYTRUDA for any severe or Grade 3
immune-mediated adverse reaction that recurs and for any
life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may 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.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for
adverse reactions in 6% of 89 patients who received the recommended dose
of 2 mg/kg and 9% of 411 patients across all doses studied. Serious
adverse reactions occurred in 36% of patients receiving KEYTRUDA. The
most frequent serious adverse drug reactions reported in 2% or more of
patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were
fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%),
decreased appetite (26%), constipation (21%), arthralgia (20%), and
diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an
intravenous infusion over 30 minutes every three weeks until disease
progression or unacceptable toxicity. No formal pharmacokinetic drug
interaction studies have been conducted with KEYTRUDA. 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. Safety and effectiveness of KEYTRUDA have not
been established in pediatric patients.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the
uncontrolled growth of pigment-producing cells. The incidence of
melanoma has been increasing over the past four decades – approximately
232,130 new cases were diagnosed worldwide in 2012. In the U.S.,
melanoma is one of the most common types of cancer diagnosed and is
responsible for the vast majority of skin cancer deaths. In 2014, an
estimated 76,100 people were expected to be diagnosed and an estimated
9,710 people were expected to die of the disease in the U.S. alone. The
five-year survival rates for advanced or metastatic melanoma (Stage IV)
are estimated to be 15 to 20 percent.

Our Focus on Cancer

Our goal is to translate breakthrough science into biomedical
innovations to help people with cancer worldwide. For Merck Oncology,
helping people fight cancer is our passion, supporting accessibility to
our cancer medicines is our commitment, and pursuing research in
immuno-oncology is our focus to potentially bring new hope to people
with cancer. For more information about our oncology clinical trials,
visit www.merck.com/clinicaltrials.

About Merck

Today’s Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
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 healthcare through
far-reaching policies, programs and partnerships. For more information,
visit www.merck.com
and connect with us on Twitter,
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Forward-Looking Statement

This news release includes “forward-looking statements” within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. These statements are based
upon the current beliefs and expectations of Merck’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 healthcare legislation in the
United States and internationally; global trends toward healthcare cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; Merck’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 Merck’s patents and other protections
for innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.

Merck 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 Merck’s 2014 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 (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and the Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.

Merck
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