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April 19, 2015 7:30 am ET

Data Formed the Basis for KEYTRUDA U.S. FDA Submission and Breakthrough Therapy Designation in Advanced NSCLC

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced new data from KEYNOTE-001, a Phase 1b study evaluating
KEYTRUDA^® (pembrolizumab), the company’s anti-PD-1 therapy,
in naïve and previously-treated patients with advanced non-small cell
lung cancer (NSCLC). In an analysis of 313 patients from a validation
data set for tumor PD-L1 expression, overall-response rate (ORR) was
45.2 percent¹ (95% CI, 33.5-57.3) in patients with greater
than or equal to (≥) 50 percent of tumor cells positive for PD-L1
expression (n=73). In the other PD-L1 subgroups, ORR was 16.5 percent
(95% CI, 9.9-25.1) in patients with 1-49 percent tumor cells positive
(n=103) and 10.7 percent (95% CI, 2.3-28.2) in patients with less than 1
percent tumor cells positive (n=28) for PD-L1 expression. In the total
study population, ORR was 19.4 percent (95% CI, 16.0-23.2) (n=495),
which was consistent with data previously presented from this study.
These data from KEYNOTE-001 will be presented today by Dr. Edward Garon,
Jonsson Comprehensive Cancer Center, University of California, Los
Angeles at the American Association for Cancer Research (AACR) Annual
Meeting (abstract #CT104), were part of the AACR press program, and were
also published today in the New England Journal of Medicine.

The efficacy findings demonstrated that tumor PD-L1 expression may be a
relevant biomarker for the identification of NSCLC patients with an
enhanced likelihood of experiencing improved efficacy with an anti-PD-1
therapy. PD-L1 is a protein that may be overexpressed in the tumor and
may contribute mechanistically to an inhibited immune response.

“In this study, NSCLC patients whose tumors express PD-L1 in the
majority of their cells experienced the highest response rates to
KEYTRUDA treatment,” said Dr. Roger Perlmutter, president, Merck
Research Laboratories. “The results from this study formed the basis for
our Breakthrough Therapy designation and our recent FDA submission for
advanced NSCLC, and indicate that tumor PD-L1 expression may be a
relevant biomarker to identify patients more likely to have higher rates
of response to KEYTRUDA in this tumor type.”

Merck recently announced that the company submitted a supplemental
Biologics License Application (sBLA) for KEYTRUDA in advanced NSCLC with
the U.S. Food and Drug Administration (FDA). (link)
Under PDUFA, the FDA has 60 days from submission of the sBLA to
determine if the application will be accepted for review. KEYTRUDA was
granted Breakthrough Therapy designation in advanced NSCLC by the U.S
Food and Drug Administration (FDA) in October 2014.

Additional Findings from KEYNOTE-001 for the Total Evaluable
Population

Data for progression-free survival (PFS) and overall survival (OS) based
on tumor PD-L1 expression was also presented in 356 naïve and
previously-treated patients with advanced NSCLC (total evaluable for
PD-L1 staining). In the ≥50 percent PD-L1 sub-group, median PFS (95% CI)
was 6.3 months (2.9-12.5) (n=119); within this group, PFS was 6.1 months
(2.1-12.5) for previously-treated patients (n=294) and 12.5 months
(2.4-12.5) for naive patients (n=62). PFS was 3.3 months (95% CI,
2.1-4.1) in the 1-49 percent PD-L1 sub-group (n=161), and 2.3 months
(95% CI, 2.1-4.0) in less than 1 percent PD-L1 sub-group (n=76). Median
OS had not yet been reached in the ≥50 percent PD-L1 sub-group,
regardless of prior treatment. Median OS was 8.8 months for the other
PD-L1 subgroups (95% CI, 6.8-12.4 for 1-49% sub-group and 5.5-12 for
less than 1% sub-group, respectively), and was similar regardless of
prior treatment.

Median duration of response was similar across tumor PD-L1 expression
subgroups; 12.5 months (2.1+ to 23.3)² for the ≥50 percent
sub-group, 7.2 months (1.4+ to 8.3+)³ for the 1-49 percent
sub-group, and not reached (1.0+ to 10.8+)⁴ in the less than
1 percent sub-group. At the time of analysis, median follow-up duration
was 10.9 months (range, 5.2–27.5).

“These results represent the largest data set of an anti-PD-1 therapy in
naïve and previously-treated patients with advanced non-small cell lung
cancer. We are advancing a broad Phase 3 program that will further
characterize the potential benefit of KEYTRUDA compared to the standard
of care in these patients,” said Roger Dansey, therapeutic area head and
senior vice president, oncology late-stage development, Merck Research
Laboratories.

Adverse events evaluated in the total study population were consistent
with previously reported safety data for KEYTRUDA. The most common
treatment-related adverse events were fatigue, pruritus, and decreased
appetite. Grade 3-5 treatment-related adverse events occurred in 9.5
percent of patients (n=47). Treatment-related adverse events of an
inflammatory or immune-mediated nature that occurred in more than 2
percent of patients were infusion-related reactions (n=15; 3.0%),
hypothyroidism (n=34; 6.9%), and pneumonitis (n=18; 3.6%). One infusion
reaction led to treatment discontinuation and all hypothyroidism cases
were successfully managed with medical therapy. There was one
treatment-related death (pneumonitis) and grade 3-5 pneumonitis was
observed in 1.8 percent of patients (n=9). At the time of analysis, two
pneumonitis cases were ongoing (both grade 1–2).

About the KEYNOTE-001 Study and Tumor PD-L1 Validation Data Set

KEYNOTE-001 is an ongoing multi-center, single-arm, open-label Phase 1b
study evaluating KEYTRUDA in more than 1,000 patients with diverse
late-stage cancers – predominantly lung and melanoma. Three dosing
regimens were evaluated; 10mg/kg every two weeks, 10mg/kg every three
weeks or 2mg/kg every three weeks. The primary endpoints include ORR and
safety; the secondary endpoints include PFS, OS and duration of
response. Tumor response was assessed every 9 weeks per RECIST 1.1 by
independent, central, blinded radiographic review. For the tumor PD-L1
expression validation data set, tumor samples were contemporaneously
collected within six months of staining and tumor PD-L1 expression was
measured by Dako’s immunohistochemistry companion diagnostic test PD-L1
IHC 22C3 PharmDx. The training data set for tumor PD-L1 expression from
KEYNOTE-001 was presented at the AACR Annual Meeting in April 2014.

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 more than 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 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 lung cancer (NSCLC) and small cell lung cancer
(SCLC). NSCLC is the most common type of lung cancer, accounting for
about 85 percent of all cases. The five-year relative survival rate for
all advanced or metastatic (Stage IV) lung cancers combined is estimated
to be four percent.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on
many types of cells, including some cancer cells. Under normal
conditions, the interaction of PD-L1 with another protein, called
programmed death receptor-1 (PD-1), serves as an important immune system
checkpoint, keeping the immune system in balance and preventing the body
from attacking its own cells when inflammation or an infection is
present. When cancerous tumors express PD-L1, however, they are able to
escape detection and destruction by cytotoxic T-cells – a type of
cancer-killing immune cell – allowing the tumor to survive and grow.
Tumor PD-L1 expression has been observed at varying levels across many
tumor types, including breast, lung and bladder cancer. High levels of
PD-L1 expression, called overexpression, are under investigation for
potential use as a way to help identify patients with an enhanced
likelihood to respond to certain immune-based treatment approaches.

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,
Facebook
and YouTube.

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.

____________________________

¹ Original release distributed on Sunday, April 19, 2015
listed ORR as 45.4 percent; Release corrected on Wednesday, May 20, 2015
to reflect ORR of 45.2 percent

² Original release distributed on Sunday, April 19, 2015
listed median duration of response for the ≥50 percent PD-L1 expression
sub-group as 12.4 months (2+ to 22.8+); Release corrected on Wednesday,
May 20, 2015 to reflect median duration of response for the ≥50 percent
PD-L1 expression sub-group as 12.5 months (2.1+ to 23.3)

³ Original release distributed on Sunday, April 19, 2015
listed median duration of response for the 1-49 percent PD-L1 expression
sub-group as 10.3 months (1.4+ to 10.3+); Release corrected on
Wednesday, May 20, 2015 to reflect median duration of response for the
1-49 percent PD-L1 expression sub-group as 7.2 months (1.4+ to 8.3+)

⁴ Original release distributed on Sunday, April 19, 2015
listed median duration of response for the less than 1 percent PD-L1
expression sub-group as not reached (0.9+ to 10.8+); Release corrected
on Wednesday, May 20, 2015 to reflect median duration of response for
the less than 1 percent PD-L1 expression sub-group as not reached (1.0+
to 10.8+)

Media:
Pamela Eisele, 267-305-3558
Claire Mulhearn, 908-236-1118
or
Investors:
Joseph Romanelli, 908-740-1986
Justin Holko, 908-740-1879