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July 22, 2015 6:00 am ET

KEYTRUDA Demonstrated Superior Survival versus Ipilimumab in a Phase 3 Clinical Trial

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the European Commission has approved KEYTRUDA^®
(pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of
advanced (unresectable or metastatic) melanoma in adults. The European
Commission approval of KEYTRUDA is based on data from three clinical
studies conducted in more than 1,500 first-line and previously-treated
patients with advanced melanoma. KEYTRUDA received European Commission
regulatory approval based on Phase 3 data which showed it is the first
and only anti-PD-1 therapy to provide a statistically superior survival
benefit as a monotherapy compared to ipilimumab, the current standard of
care for advanced melanoma. Today’s approval allows marketing of
KEYTRUDA in all 28 EU member states at the approved dose of 2 mg/kg
every three weeks.

“Today’s European approval supports our goal of accelerating
immuno-oncology research for the benefit of patients around the world,”
said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.
“We believe that the broad data set supporting this approval helps
illustrate the significant potential of KEYTRUDA to treat advanced
melanoma, a devastating disease.”

“Merck has long-believed that innovation and access must go
hand-in-hand, which is why we work to bring forward new innovations, and
ensure access to those innovations,” said Deepak Khanna, senior vice
president and regional president, Europe, MSD Oncology. “Merck is
committed to working collaboratively with governments and other
stakeholders to ensure that KEYTRUDA will be made available to advanced
melanoma patients in Europe as rapidly as possible.”

About KEYNOTE-001, 002 and 006

The European Commission’s approval is based on data from three studies
— KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006. These studies evaluated the
efficacy and safety of KEYTRUDA in advanced melanoma patients – across
treatment lines, prognostic factors, tumor characteristics, and BRAF
mutational status – and established 2 mg/kg every three weeks as the
approved dose.

KEYNOTE-001, the largest Phase 1b study to date of an anti-PD-1
antibody, is a single arm, open label study of KEYTRUDA (2 mg/kg every
three weeks or 10 mg/kg every two or three weeks) that included patients
with advanced melanoma who were previously-treated with ipilimumab (and,
if BRAF V600 mutation-positive, a BRAF or MEK inhibitor) and patients
who were ipilimumab-naïve. In two cohorts of advanced melanoma patients
comparing doses of KEYTRUDA, of the 140 patients receiving the approved
2 mg/kg every three week dose, the overall response rate (ORR) (primary
endpoint) for KEYTRUDA was 33 percent in ipilimumab-naïve patients (95%
CI, 21, 48) (n=51) and 25 percent in patients previously-treated with
ipilimumab (95% CI, 16, 35) (n=89). The secondary endpoints were overall
survival (OS), progression-free survival (PFS), and duration of response
per RECIST v1.1. Results were similar across dosing schedules.

KEYNOTE-002 is a Phase 2, multi-center, randomized study of KEYTRUDA (2
mg/kg every three weeks or 10 mg/kg every three weeks) compared to
investigator-choice chemotherapy in 540 patients with advanced melanoma
who were previously-treated with ipilimumab and, if BRAF V600 mutation
positive, a BRAF or MEK inhibitor. The primary endpoints were PFS and
OS. Both KEYTRUDA doses evaluated were superior compared to chemotherapy
for PFS at both six-months and nine-months, with PFS rates of 34 and 24
percent, respectively, for the 2 mg/kg dose (95% CI, 0.57 [0.45, 0.73])
(n=180) and 38 and 29 percent for the 10 mg/kg dose (95% CI, 0.50 [0.39,
0.64]) (n=181), compared to 16 and 8 percent for investigator-choice
chemotherapy (n=179). OS data were not mature at the time of the
analysis. The secondary endpoints were ORR and duration of response per
RECIST v1.1.

KEYNOTE-006 is a Phase 3, multi-center, randomized, study of KEYTRUDA
(10 mg/kg every two or three weeks) compared to ipilimumab in 834
patients with advanced melanoma. In the planned interim analysis of the
co-primary endpoints, KEYTRUDA demonstrated superior PFS and OS compared
to ipilimumab. The estimated 6-month and 9-month PFS rates for KEYTRUDA
were 47 and 40 percent, respectively, for the 2-week group (95% CI, 0.58
[0.46, 0.72], p<0.00001) (n=279) and 46 and 42 percent for the 3-week
group (95% CI, 0.58 [0.47, 0.72], p<0.00001) (n=277), compared to 27 and
16 percent for ipilimumab (n=278). One-year OS for KEYTRUDA was 74
percent (2-week group) (95% CI, 0.63 [0.47, 0.83], p = 0.00052) and 68
percent (3-week group) (95% CI, 0.69 [0.52, 0.90], p = 0.00358),
compared to 58 percent for ipilimumab. The risk of death was reduced by
31 percent for patients treated with KEYTRUDA in the 3-week group
(hazard ratio 0.69) and 37 percent in the 2-week group (hazard ratio
0.63). The secondary endpoints were ORR and duration of response per
RECIST v1.1.

The safety analysis supporting the European approval of KEYTRUDA was
based on 1,012 advanced melanoma patients across three doses (2 mg/kg
every three weeks or 10 mg/kg every two or three weeks) in studies
KEYNOTE-001 and KEYNOTE-002 combined. The most common adverse reactions
(>10%) with KEYTRUDA were diarrhea (15%), nausea (12%), pruritus (25%),
rash (25%), arthralgia (13%) and fatigue (33%). The majority of adverse
reactions reported were of Grade 1 or 2 severity. The most serious
adverse reactions were immune-related adverse reactions and severe
infusion-related reactions.

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. In Europe,
approximately 100,000 new cases were estimated to be diagnosed in 2012,
which is almost half of the global incidence of melanoma. The five-year
survival rates for advanced or metastatic melanoma (Stage IV) are
estimated to be 15 to 20 percent in the United States and 5 to 22
percent in Europe.

About KEYTRUDA

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.

With the European Commission decision, KEYTRUDA is now approved in more
than 35 countries for the treatment of advanced melanoma. Merck is
advancing a broad and fast-growing clinical development program for
KEYTRUDA with more than 100 clinical trials – across more than 30 tumor
types and enrolling more than 16,000 patients – both as a monotherapy
and in combination with other therapies.

U.S. Indication for KEYTRUDA^® (pembrolizumab)

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.

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.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck Oncology,
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. 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
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and YouTube.

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 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.

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