Merck Receives Accelerated Approval of KEYTRUDA® (pembrolizumab), the First FDA-Approved Anti-PD-1 Therapy
September 4, 2014 2:15 pm ET
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved KEYTRUDA® (pembrolizumab) at a dose of 2 mg/kg 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
KEYTRUDA is the first anti-PD-1 (programmed death receptor-1) therapy
approved in the United States and received FDA’s Breakthrough Therapy
designation for advanced melanoma, which was granted based on the
significance of early study findings and the unmet medical need. For the
recommended 2 mg/kg dose based on data in 89 patients, the overall
response rate was 24 percent (95% CI: 15, 34), with one complete
response and 20 partial responses (21/89). At the time of analysis, 86
percent (18/21) of patients with objective responses had ongoing
responses with durations ranging from 1.4+ to 8.5+ months, including
eight patients with ongoing responses of 6 months or longer. Fourteen
percent (3/21) had progression of disease 2.8, 2.9, and 8.2 months after
KEYTRUDA is a humanized monoclonal antibody that works by increasing the
ability of the body’s immune system to fight advanced melanoma. KEYTRUDA
blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2,
and may affect both tumor cells and healthy cells. Immune-mediated
adverse reactions occurred with KEYTRUDA including pneumonitis, colitis,
hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism.
Based on the severity of the adverse reaction, KEYTRUDA should be
withheld or discontinued and corticosteroids administered. Based on its
mechanism of action, KEYTRUDA may cause fetal harm when administered to
a pregnant woman. Female patients of reproductive potential should be
advised of the potential hazard to a fetus. For more information
regarding immune-mediated adverse reactions and use in pregnancy, see
“Selected Important Safety Information” below.
“KEYTRUDA embodies Merck’s unwavering commitment to pursue breakthrough
science to help people who are facing the most challenging diseases,”
said Kenneth C. Frazier, chairman and chief executive officer, Merck.
“We are grateful to the people with advanced melanoma who participated
in our trials, and the scientific and medical community for the shared
effort that has led to the accelerated approval of KEYTRUDA.”
“The accelerated FDA approval of KEYTRUDA is a meaningful development
for patients with advanced melanoma,” said Dr. Omid Hamid, Director of
the Melanoma Center at The Angeles Clinic and Research Institute, and a
principal investigator for the pembrolizumab melanoma clinical program.
“Our new ability to target the PD-1 pathway with KEYTRUDA is a very
exciting step in the immunotherapy field.”
Merck is conducting ongoing Phase 2 and 3 clinical studies in advanced
melanoma, which are designed to provide further confirmatory evidence
for KEYTRUDA in this indication. Merck plans to make KEYTRUDA available
within one week from today’s FDA approval.
Study Cohort Supporting the Accelerated FDA Approval of Single-Agent
The approval of KEYTRUDA was based on data from a multi-center,
open-label, randomized, dose-comparative study cohort of the ongoing
KEYNOTE-001 Phase 1b trial in patients with unresectable or metastatic
melanoma and progression of disease. Key eligibility criteria included
prior treatment with ipilimumab (two or more doses at 3 mg/kg or higher)
and a BRAF or MEK inhibitor, if BRAF V600 mutation positive; and disease
progression within 24 weeks following the last dose of ipilimumab.
Patients were randomized to receive 2 mg/kg (n=89) or 10 mg/kg (n=84) of
KEYTRUDA every 3 weeks until unacceptable toxicity or disease
progression. The major efficacy outcome measures were confirmed overall
response rate as assessed by blinded independent central review using
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration
of response. Tumor response was assessed every 12 weeks.
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, receiving
KEYTRUDA. 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
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.
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
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 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.
Commitment to Access for KEYTRUDA
Merck is committed to making KEYTRUDA accessible to patients.
Reimbursement support for eligible patients receiving KEYTRUDA,
including help with out-of-pocket costs and co-pay assistance, is
available through The Merck
Access Program. For eligible patients who are uninsured, financial
assistance is available through Merck’s patient assistance program. More
information is available by calling 1-855-257-3932 or visiting www.merckaccessprogram-keytruda.com.
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.
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,
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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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KEYTRUDA® is a registered trademark of Merck
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