Merck Announces Submission of Supplemental Biologics License Application (sBLA) to U.S. FDA for KEYTRUDA® (pembrolizumab) in Advanced Non-Small Cell Lung Cancer
April 19, 2015 7:00 am ET
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the company has submitted a supplemental Biologics
License Application to the U.S. Food and Drug Administration (FDA) for
KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy,
for the treatment of advanced non-small cell lung cancer (NSCLC).
KEYTRUDA previously received Breakthrough Therapy designation for
advanced NSCLC and this initial filing seeks approval in the treatment
of patients with advanced NSCLC whose disease has progressed on or after
platinum-containing chemotherapy and an FDA-approved therapy for EGFR or
ALK genomic tumor aberrations, if present. Under PDUFA, the FDA has 60
days from submission of the sBLA to determine if the application will be
accepted for review. The submission is based on data from KEYNOTE-001 in
patients with greater than or equal to 50 percent of tumor cells
positive for PD-L1 expression. These data will be presented later today
at the American Association for Cancer Research (AACR) Annual Meeting in
“We are encouraged by the new KEYNOTE-001 data evaluating KEYTRUDA in
patients with advanced non-small cell lung cancer, which will be
presented today at AACR Annual Meeting,” said Dr. Roger M. Perlmutter,
president, Merck Research Laboratories. “We look forward to the FDA’s
review of our supplemental application for KEYTRUDA, which is based in
part on these data.”
A Premarket Approval Application (PMA) was submitted by Dako North
America, Inc., an Agilent Technologies Company, for an
immunohistochemistry companion diagnostic test that detects PD-L1
expression, PD-L1 IHC 22C3 PharmDx™.
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
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
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
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
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. Unnaturally 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
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,
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.
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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 the Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
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