FDA Accepts Supplemental Biologics License Application (sBLA) for KEYTRUDA® (pembrolizumab) in Recurrent or Metastatic Head and Neck Cancer, and Grants Priority Review

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April 13, 2016 6:00 am ET

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
accepted for review the supplemental Biologics License Application
(sBLA) for KEYTRUDA® (pembrolizumab), the company’s anti-PD-1
therapy, 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. The application is seeking
approval for KEYTRUDA as a single agent at a dose of 200 mg administered
intravenously every three weeks. The FDA granted Priority Review with a
PDUFA, or target action, date of Aug. 9; the sBLA will be reviewed under
the FDA’s Accelerated Approval program.

“Starting in the early days of our development program, we have explored
the role of KEYTRUDA for patients with head and neck cancer, a
difficult-to-treat and debilitating disease with very few treatment
options,” said Roger Dansey, M.D., senior vice president and therapeutic
area head, oncology late-stage development, Merck Research Laboratories.
“We are encouraged by the data emerging from our program in this type of
cancer, and welcome today’s news as this is an important step toward
making KEYTRUDA available to these patients.”

Merck currently has the largest immuno-oncology clinical development
program in head and neck cancer and is advancing multiple
registration-enabling studies with KEYTRUDA as a single agent and in
combination with chemotherapy.

About KEYTRUDA® (pembrolizumab) Injection
100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA 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.

KEYTRUDA is indicated in the United States for the treatment of patients
with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic
non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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. The NSCLC
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.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion
over 30 minutes every three weeks for the approved indications.

About Head and Neck Cancer

Head and neck cancer describes a number of different tumors that develop
in or around the throat, larynx, nose, sinuses and mouth. Most head and
neck cancers are squamous cell carcinomas that begin in the flat,
squamous cells that make up the thin surface layer of the structures in
the head and neck. The leading modifiable risk factors for head and neck
cancer include tobacco and heavy alcohol use. Other non-modifiable risk
factors include infection with certain types of HPV, also called human
papillomaviruses
. Each year, worldwide, there are approximately
400,000 cases of cancer of the oral cavity and pharynx, in addition to
approximately 160,000 cases of cancer of the larynx, resulting in
approximately 300,000 deaths. In the U.S. approximately 62,000 new cases
of cancer of the oral cavity, pharynx and larynx are estimated to be
diagnosed in 2016.

Selected Important Safety Information for KEYTRUDA® (pembrolizumab)

Immune-mediated pneumonitis, including fatal cases, occurred in patients
receiving KEYTRUDA. Pneumonitis occurred in 32 (2%) of 1,567 patients
with melanoma, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%)
pneumonitis. Pneumonitis occurred in 19 (3.5%) of 550 patients with
non-small cell lung cancer (NSCLC), including Grade 2 (1.1%), 3 (1.3%),
4 (0.4%), or 5 (0.2%) pneumonitis and more frequently in patients with a
history of asthma/chronic obstructive pulmonary disease (5.4%) or prior
thoracic radiation (6.0%). Monitor patients for signs and symptoms of
pneumonitis. Evaluate suspected pneumonitis with radiographic imaging.
Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold
KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA
for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 31 (2%) of 1,567 patients with
melanoma, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis.
Immune-mediated colitis occurred in 4 (0.7%) of 550 patients with NSCLC,
including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs
and symptoms of colitis. Administer corticosteroids for Grade 2 or
greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently
discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in 16 (1%) of 1,567 patients with
melanoma, including Grade 2 (0.1%), 3 (0.7%), 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.

Hypophysitis occurred in 13 (0.8%) of 1,567 patients with melanoma,
including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis.
Hypophysitis occurred in 1 (0.2%) of 550 patients with NSCLC, which was
Grade 3 in severity. 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.

Hyperthyroidism occurred in 51 (3.3%) of 1,567 patients with melanoma,
including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism
occurred in 127 (8.1%) of 1,567 patients with melanoma, including Grade
3 (0.1%) hypothyroidism. Hyperthyroidism occurred in 10 (1.8%) of 550
patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%)
hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients
with NSCLC, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. 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 replacement
hormones for hypothyroidism and manage hyperthyroidism with thionamides
and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for
Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3
(0.1%) of 2,117 patients. Monitor patients for hyperglycemia or other
signs and symptoms of diabetes. Administer insulin for type 1 diabetes,
and withhold KEYTRUDA (pembrolizumab) and administer anti-hyperglycemics
in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in 7 (0.4%) of 1,567 patients with
melanoma, including Grade 2 (0.2%), 3 (0.2%) and Grade 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.

Other clinically important immune-mediated adverse reactions can occur.
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 immune-mediated 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 1567 patients
with melanoma: arthritis (1.6%), exfoliative dermatitis, bullous
pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia
gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures
arising in a patient with inflammatory foci in brain parenchyma. The
following clinically significant, immune-mediated adverse reactions
occurred in less than 1% of 550 patients with NSCLC: rash, vasculitis,
hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been
reported in 3 (0.1%) of 2,117 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.

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 Trial 6, KEYTRUDA (pembrolizumab) 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 Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of
357 patients with advanced melanoma; the most common (≥1%) were general
physical health deterioration (1%), asthenia (1%), dyspnea (1%),
pneumonitis (1%), and generalized edema (1%). Adverse reactions leading
to interruption of KEYTRUDA occurred in 14% of patients; the most common
(≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%).
The most common adverse reactions with KEYTRUDA vs. chemotherapy were
fatigue (43% with KEYTRUDA), pruritus (28% vs. 8%), rash (24% vs. 8%),
constipation (22% vs. 20%), nausea (22% with KEYTRUDA), diarrhea (20%
vs. 20%), and decreased appetite (20% with KEYTRUDA). Corresponding
incidence rates are listed for chemotherapy only for those adverse
reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 14% of 550
patients with NSCLC. Serious adverse reactions occurred in 38% of
patients. The most frequent serious adverse reactions reported in 2% or
more of patients were pleural effusion, pneumonia, dyspnea, pulmonary
embolism, and pneumonitis. The most common adverse reactions (reported
in at least 20% of patients) were fatigue (44%), decreased appetite
(25%), cough (29%), and dyspnea (23%).

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 and for 4 months after the final dose.

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

For 125 years, Merck has been a global health care 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
health care through far-reaching policies, programs and partnerships.
For more information, visit www.merck.com
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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
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The company undertakes no obligation to publicly update any
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statements can be found in the company’s 2015 Annual Report on Form 10-K
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Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and

Patient Information/Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.

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