Merck Provides Additional Update: FDA
Extends Action Date for Additional sBLA in Ipilimumab-Refractory
Advanced Melanoma
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced the U.S. Food and Drug Administration (FDA)
has accepted for review a supplemental Biologics License
Application (sBLA) for KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1
therapy. Merck is seeking approval for KEYTRUDA, at the currently
approved dose of 2 mg/kg every three weeks, for the first-line
treatment of unresectable or metastatic melanoma patients. The FDA
granted Priority Review with a PDUFA, or target action, date of
December 19, 2015. Additionally, the FDA has extended the action
date for a separate sBLA for KEYTRUDA for the treatment of patients
with ipilimumab-refractory advanced melanoma. The new action date
is now December 24, 2015.
“Through our clinical program for KEYTRUDA we have accumulated
substantial data on the role of our anti-PD-1 therapy in advanced
melanoma. We look forward to the FDA's review of each of these
applications, and to delivering on our goal of helping patients
with advanced melanoma to achieve long-term disease control and
survival,” said Dr. Roger M. Perlmutter, president, Merck Research
Laboratories.
KEYTRUDA is currently 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.
The sBLA submission for first-line use in advanced melanoma was
based in part on data from KEYNOTE-006, a Phase 3 study which
evaluated KEYTRUDA in 834 patients with unresectable or metastatic
melanoma with progression of disease. Findings from this study were
presented at the 2015 American Associated for Cancer Research
(AACR) Annual Meeting and published in the New England Journal of
Medicinei.
Update on sBLA in Ipilimumab-Refractory Advanced
Melanoma
The sBLA for ipilimumab-refractory advanced melanoma included
data from KEYNOTE-002. KEYNOTE-002 is the Phase 2 study which
demonstrated KEYTRUDA was superior to chemotherapy in helping more
patients with ipilimumab-refractory advanced melanoma achieve
progression-free survival (PFS). In an effort to provide the FDA
with the most robust data for KEYTRUDA in this population, Merck
submitted an additional analysis from KEYNOTE-002. The submission
constitutes a major amendment which will require additional time
for review.
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.
Merck is advancing a broad and fast-growing clinical development
program for KEYTRUDA with more than 100 clinical trials – across
more than 30 tumor types and enrolling more than 16,000 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, 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 (pembrolizumab). 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
(including hypopituitarism and adrenal insufficiency). 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.
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.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has
occurred in patients receiving KEYTRUDA. Monitor patients for
hyperglycemia and other signs and symptoms of diabetes. Administer
insulin for type 1 diabetes, and withhold KEYTRUDA in cases of
severe hyperglycemia until metabolic control is achieved.
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 (pembrolizumab) for Grade 2;
permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
Other clinically important immune-mediated adverse reactions can
occur. The following clinically significant, immune-mediated
adverse reactions occurred in patients treated with KEYTRUDA
(pembrolizumab): exfoliative dermatitis, uveitis, arthritis,
myositis, pancreatitis, hemolytic anemia, partial seizures arising
in a patient with inflammatory foci in brain parenchyma, severe
dermatitis including bullous pemphigoid, 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.
Infusion-related reactions, including severe and
life-threatening reactions, have occurred in patients receiving
KEYTRUDA. Monitor patients for signs and symptoms of
infusion-related reactions including rigors, chills, wheezing,
pruritus, flushing, rash, hypotension, hypoxemia, and fever. For
severe or life-threatening reactions, stop infusion and permanently
discontinue KEYTRUDA.
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 9% of 411 patients across all
doses studied. Adverse reactions, reported in at least two
patients, that led to discontinuations of KEYTRUDA were:
pneumonitis, renal failure, and pain. 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 (pembrolizumab). 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 Melanoma
Melanoma, the most serious form of skin cancer, is characterized
by the uncontrolled growth of pigment-producing cells. The
incidence of melanoma has been increasing over the past four
decades – approximately 232,000 new cases were diagnosed worldwide
in 2012. In the U.S., melanoma is one of the most common types of
cancer diagnosed and is responsible for the vast majority of skin
cancer deaths. In 2015, an estimated 73,870 people are expected to
be diagnosed and an estimated 9,940 people are expected to die of
the disease in the U.S. alone. The five-year survival rates for
advanced or metastatic melanoma (Stage IV) are estimated to be 15
to 20 percent.
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
Today’s Merck is 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 and YouTube.
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 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 health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’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 the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company 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 the company’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
_______________________________________
i Robert C, et al. Pembrolizumab versus Ipilimumab in
Advanced Melanoma. N Engl J Med 2015; 372:2521-2532
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