Merck Receives Positive CHMP Opinion for KEYTRUDA® (pembrolizumab) for the Treatment of Advanced Melanoma
May 22, 2015 6:12 am ET
Opinion for KEYTRUDA Based on Efficacy and Safety Data in More than 1,500 Patients with Advanced Melanoma as Both First-Line Therapy and in those Previously Treated
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the Committee for Medicinal Products for Human Use
(CHMP) of the European Medicines Agency (EMA) has adopted a positive
opinion recommending approval of KEYTRUDA® (pembrolizumab),
the company’s anti-PD-1 therapy, for the treatment of advanced
(unresectable or metastatic) melanoma, as both first-line therapy and in
previously treated patients. The CHMP positive opinion for KEYTRUDA,
which is based on data in more than 1,500 adult patients with advanced
melanoma, will now be reviewed by the European Commission for central
marketing authorization in the European Union (EU).
“Merck is committed to bringing KEYTRUDA to people with advanced
melanoma in Europe as rapidly as possible, and the positive CHMP opinion
marks a significant step forward,” said Roger Dansey, therapeutic area
head and senior vice president, oncology late stage development, Merck
Research Laboratories. “We have established a broad data set for
KEYTRUDA in the treatment of advanced melanoma, and have demonstrated
improvements in progression free survival compared to chemotherapy and a
survival benefit compared to ipilimumab. We look forward to working with
European health authorities to make KEYTRUDA available to patients.”
Pembrolizumab, which will be marketed under the worldwide brand name of
KEYTRUDA, is one of the first of a new generation of immunotherapies
that works by blocking the PD-1 pathway. KEYTRUDA was the first
anti-PD-1 therapy approved in the United States and the first medicine
to be accepted under the UK’s Early Access to Medicines Scheme (EAMS),
which was introduced to help patients benefit from promising, innovative
treatments before a European license has been granted.
Data Supporting the CHMP Positive Opinion
The positive opinion was based on data from more than 1,500 patients
with advanced melanoma treated with KEYTRUDA as monotherapy in three
studies – from a large Phase 1b study, KEYNOTE-001; from a randomized,
controlled study KEYNOTE-002; and an interim analysis from a second,
randomized, controlled study, KEYNOTE-006. In KEYNOTE-001, the largest
Phase 1b study to date of an anti-PD-1 antibody, KEYTRUDA demonstrated
durable objective responses in patients with advanced melanoma.
KEYNOTE-002, a Phase 2 study, showed KEYTRUDA was superior to
chemotherapy for progression-free survival in ipilimumab refractory
advanced melanoma. KEYNOTE-006, a Phase 3 study, showed KEYTRUDA was
superior to ipilimumab for overall survival, progression-free survival,
and overall response rate. The trial was stopped early in March 2015
based on the recommendation of the study’s independent Data Monitoring
Committee as it had met its two primary endpoints. The CHMP recommended
approval of KEYTRUDA monotherapy at a dose of 2 mg/kg every three weeks,
which is the currently approved dose for advanced melanoma in the U.S.
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. In 2012,
approximately 232,130 new cases were diagnosed worldwide, and the
incidence in Europe was estimated to be 100,300. The five-year survival
rates for advanced or metastatic melanoma (Stage IV) are estimated to be
15 to 20 percent.
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 over 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.
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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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