Submission Based on Data from KEYNOTE-021
Trial, Cohort G, Which Enrolled Patients Regardless of PD-L1
Expression
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, plus chemotherapy (pemetrexed plus carboplatin)
for the first-line treatment of patients with metastatic or
advanced non-squamous non-small cell lung cancer (NSCLC) regardless
of PD-L1 expression and with no EGFR or ALK genomic tumor
aberrations.
This is the first application for regulatory approval of
KEYTRUDA in combination with another treatment. The FDA granted
Priority Review with a PDUFA, or target action, date of May 10,
2017. The sBLA will be reviewed under the FDA’s Accelerated
Approval program.
“Through our monotherapy and combination studies, we are working
to find new approaches to help a broad range of patients with lung
cancer,” said Dr. Roger Dansey, senior vice president and
therapeutic area head, oncology late-stage development, Merck
Research Laboratories. “KEYTRUDA in combination with chemotherapy
has shown promise versus chemotherapy alone in the first-line
treatment of non-squamous metastatic non-small cell lung cancer,
regardless of PD-L1 levels. If approved, this could be the first
regimen combining chemotherapy with an immuno-oncology agent for
patients with advanced non-small cell lung cancer.”
The application seeks accelerated approval for KEYTRUDA at a
fixed dose of 200 mg administered intravenously every three weeks
in combination with pemetrexed 500 mg/m2 administered as an IV
infusion over 10 minutes every three weeks, and carboplatin AUC 5
mg/mL/min every three weeks for four cycles. KEYNOTE-021, Part 2,
Cohort G, the pivotal cohort that forms the basis of the
submission, studied 123 previously untreated patients with
metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor
aberrations and regardless of PD-L1 expression.
KEYTRUDA (pembrolizumab) is currently approved in lung cancer
for the first-line treatment of patients with metastatic NSCLC
whose tumors have high PD-L1 expression (tumor proportion score
[TPS] of 50 percent or more) as determined by an FDA-approved test,
with no EGFR or ALK genomic tumor aberrations; and for the
treatment of patients with metastatic NSCLC whose tumors express
PD-L1 (TPS of one percent or more) 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.
Merck has an extensive development program in NSCLC and is
currently advancing multiple registration-enabling studies with
KEYTRUDA as monotherapy and in combination with other
treatments.
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 and small cell. NSCLC
is the most common type of lung cancer, accounting for about 85
percent of all cases. The five-year survival rate for patients
suffering from highly advanced, metastatic (Stage IV) lung cancers
is estimated to be two percent.
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 use vial.
KEYTRUDA® (pembrolizumab) Indications
and Dosing
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 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.
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 (pembrolizumab) 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. The incidence of new or
worsening hypothyroidism was higher in patients with HNSCC
occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3
(0.5%) 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 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 (pembrolizumab) 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.
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.
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 KEYNOTE-006, KEYTRUDA 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 (pembrolizumab)
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 KEYNOTE-002, 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 maculopapular 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 8% of 682
patients with metastatic NSCLC. The most common adverse event
resulting in permanent discontinuation of KEYTRUDA was pneumonitis
(1.8%). Adverse reactions leading to interruption of KEYTRUDA
occurred in 23% of patients; the most common (≥1%) were diarrhea
(1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation
(1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most
common adverse reactions (occurring in at least 20% of patients and
at a higher incidence than with docetaxel) were decreased appetite
(25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).
KEYTRUDA was discontinued due to adverse reactions in 17% of 192
patients with HNSCC. Serious adverse reactions occurred in 45% of
patients. The most frequent serious adverse reactions reported in
at least 2% of patients were pneumonia, dyspnea, confusional state,
vomiting, pleural effusion, and respiratory failure. The most
common adverse reactions (reported in at least 20% of patients)
were fatigue, decreased appetite, and dyspnea. Adverse reactions
occurring in patients with HNSCC were generally similar to those
occurring in patients with melanoma or NSCLC, with the exception of
increased incidences of facial edema (10% all Grades; 2.1% Grades 3
or 4) and new or worsening hypothyroidism.
It is not known whether KEYTRUDA (pembrolizumab) 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,
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 more than 400 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 over a century, 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 and connect with us on Twitter, Facebook, YouTube and
LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
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USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
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the products will receive the necessary regulatory approvals or
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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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