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May 5, 2017 6:00 am ET

First Approval for KEYTRUDA in a Hematologic Malignancy in the EU

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
adult patients with relapsed or refractory classical Hodgkin lymphoma
(cHL) who have failed autologous stem cell transplant (ASCT) and
brentuximab vedotin (BV), or who are transplant-ineligible and have
failed BV. The approval allows marketing of KEYTRUDA in all 28 EU member
states plus Iceland, Lichtenstein and Norway, at the approved dose of
200 mg every three weeks until disease progression or unacceptable
toxicity.

“Today’s approval brings an important new treatment option to patients
in Europe with classical Hodgkin lymphoma who have not responded to
existing therapies,” said Dr. Roger Dansey, senior vice president and
therapeutic area head, oncology late-stage development, Merck Research
Laboratories. “This milestone underscores our commitment to evaluating
KEYTRUDA in diseases with unmet need facing the hematology community.”

“For patients with classical Hodgkin lymphoma who have not been
successfully treated with prior therapies – many of whom are young and
have a poor prognosis – there are limited options and treating the
disease poses significant challenges,” said Pier Luigi Zinzani, M.D.,
Ph.D., associate professor of hematology, Institute of Hematology “L. e
A. Seràgnoli,” University of Bologna. “With this approval, we will now
be able to provide these patients with a much-needed new treatment
option.”

Data Supporting the Approval

The approval was based on data in 241 patients from the KEYNOTE-087 and
KEYNOTE-013 trials. These multicenter, open-label studies evaluated
patients with cHL who failed ASCT and BV, who were ineligible for ASCT
because they were unable to achieve a complete or partial remission
after salvage chemotherapy and failed BV, or who failed ASCT and did not
receive BV. Both studies included patients regardless of PD-L1
expression. Patients with active, non-infectious pneumonitis, an
allogeneic transplant within the past five years (or more than five
years but with graft-versus-host-disease [GVHD]), active autoimmune
disease or a medical condition that required immunosuppression were
ineligible for either trial. The major efficacy outcome measures,
overall response rate (ORR) and complete remission rate (CRR), were
assessed by blinded independent central review according to the 2007
revised International Working Group (IWG) criteria. Secondary efficacy
outcome measures were duration of response, progression-free survival,
and overall survival.

In KEYNOTE-087, 210 patients received KEYTRUDA (pembrolizumab) at a dose
of 200 mg every three weeks until unacceptable toxicity or documented
disease progression. Eighty-one percent of patients were refractory to
at least one prior therapy, including 35 percent who were refractory to
first-line therapy. Additionally, 61 percent of patients had undergone
prior ASCT, 38 percent were transplant ineligible; 17 percent had no
prior BV use and 36 percent of patients had prior radiation therapy.
Efficacy analysis showed an ORR of 69 percent (95% CI: 62.3, 75.2) with
a CRR of 22 percent and a partial remission rate (PRR) of 47 percent.
The median follow-up time was 10.1 months. Among the 145 responding
patients, the median duration of response was 11.1 months (range 0.0+ to
11.1), with 76 percent of responding patients having responses of six
months or longer.

In KEYNOTE-013, 31 patients received KEYTRUDA at a dose of 10 mg/kg
every two weeks until unacceptable toxicity or documented disease
progression. Eighty-seven percent of patients were refractory to at
least one prior therapy, including 39 percent who were refractory to
first-line therapy. Seventy-four percent of patients had undergone prior
ASCT, 26 percent were transplant ineligible, and 42 percent of patients
had prior radiation therapy. Efficacy analysis showed an ORR of 58
percent (95% CI: 39.1, 75.5) with a CRR of 19 percent and a PRR of 39
percent. The median follow-up time was 28.7 months. Among the
18 responding patients, the median duration of response was not reached
(range 0.0+ to 26.1+), with 80 percent of patients with a response of
six months or longer and 70 percent of patients with a response of 12
months or longer.

The safety analysis supporting the European approval of KEYTRUDA
(pembrolizumab) was based on 3,194 patients with advanced melanoma,
NSCLC or cHL across four doses (2 mg/kg every three weeks, 200 mg every
three weeks, or 10 mg/kg every two or three weeks) in clinical studies.
The most common adverse reactions (greater than 10%) with KEYTRUDA were
fatigue (22%), pruritus (15%), rash (13%), diarrhea (12%) and
nausea (10%). 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 Hodgkin Lymphoma

Hodgkin lymphoma is a type of lymphoma that develops in the white blood
cells, called lymphocytes, which are part of the immune system. Hodgkin
lymphoma can start almost anywhere – most often in lymph nodes in the
upper part of the body, with the most common sites being in the chest,
neck or under the arms. Worldwide, there were approximately 66,000 new
cases of Hodgkin lymphoma and 25,500 people died from the disease in
2012. Classical Hodgkin lymphoma accounts for about 95 percent of all
cases of Hodgkin lymphoma in developed countries.

About KEYTRUDA

^®

(pembrolizumab)

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 administered as an intravenous infusion over 30 minutes
every three weeks for the approved indications. KEYTRUDA for injection
is supplied in a 100 mg single-dose vial.

KEYTRUDA Indications and Dosing in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a dose of 2 mg/kg every three weeks until disease
progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA (pembrolizumab) 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 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.

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.

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.

Selected Important Safety Information for KEYTRUDA

^®
 (pembrolizumab)

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. 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 (pembrolizumab) 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.

KEYTRUDA can cause other clinically important immune-mediated adverse
reactions. 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%), exfoliative dermatitis, bullous pemphigoid, rash
(1.4%), 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 cHL, 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, 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 (pembrolizumab).

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.

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.

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%).

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 of 40
pediatric patients with advanced melanoma, PD-L1–positive advanced,
relapsed, or refractory solid tumors or lymphoma, patients were treated
with KEYTRUDA for a median of 43 days (range 1 to 414 days), with 24
patients (60%) receiving treatment for 42 days or more. The safety
profile in pediatric patients was similar to that seen in adults treated
with KEYTRUDA (pembrolizumab). 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%).

Our 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 that includes nearly 500 clinical trials 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
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.

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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
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Risks and uncertainties include but are not limited to, general industry
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The company undertakes no obligation to publicly update any
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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

.

Merck
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