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), the company’s
anti-PD-1 (programmed death receptor-1) therapy, at a fixed dose of
200 mg every three weeks, 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. Under the FDA’s accelerated approval regulations,
this indication for KEYTRUDA is approved 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. For HNSCC patients,
PD-L1 testing is not needed prior to use of KEYTRUDA.
The approval is based on data from the KEYNOTE-012 study, which
included patients with recurrent or metastatic HNSCC who had
disease progression on or after platinum-containing chemotherapy or
following platinum-containing chemotherapy administered as part of
induction, concurrent, or adjuvant therapy and ECOG performance
status (PS) of zero or one. The data showed an objective response
rate (ORR) of 16 percent (95% CI: 11, 22), complete response rate
of five percent, with responses of six months or longer observed in
82 percent (n=23/28) of the responding patients. ORR and duration
of response were similar regardless of human papilloma virus (HPV)
status.
Immune-mediated adverse reactions occurred with KEYTRUDA
including pneumonitis, colitis, hepatitis, endocrinopathies, and
nephritis. Based on the severity of the adverse reaction, KEYTRUDA
should be withheld or discontinued and corticosteroids
administered. Based on its mechanism of action, KEYTRUDA can 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.
“Today’s approval represents a meaningful advance for the
oncology community, as well as for our head and neck cancer
clinical program,” said Dr. Roger M. Perlmutter, president, Merck
Research Laboratories. “Together with prior approvals in the
treatment of other tumor types, today’s action by the FDA
underscores our tireless commitment to addressing the unmet needs
of patients suffering from a broad range of cancers.”
KEYNOTE-012 was the first clinical study to investigate the role
of a PD-1 inhibitor in patients with recurrent or metastatic HNSCC
with disease progression on or after platinum-containing
chemotherapy. Merck currently has the largest immuno-oncology
clinical development program, including multiple
registration-enabling studies in head and neck cancer, and is
conducting research investigating KEYTRUDA (pembrolizumab) as a
monotherapy, as well as in combination with chemotherapy compared
to the current standard of care.
“Head and neck cancer is a complex disease that historically has
been associated with high recurrence rates and poor long-term
outcomes, highlighting the critical need for new treatment
options,” said Dr. Tanguy Seiwert, associate director of the Head
and Neck Cancer Program and assistant professor of medicine at The
University of Chicago. “The approval of KEYTRUDA for previously
treated patients with recurrent or metastatic head and neck
squamous cell carcinoma is an important step forward in treating
this disease.”
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.
“Head and neck squamous cell carcinoma presents unique
challenges including limited treatment options, especially for
patients with recurrent or metastatic disease,” said Holly Boykin,
executive director, Head and Neck Cancer Alliance. “We welcome the
approval of KEYTRUDA as a new treatment option for people whose
lives are impacted by this devastating disease.”
Data Supporting the Approval
The accelerated FDA approval was based on a multicenter,
nonrandomized, open-label, multi-cohort phase 1b study,
KEYNOTE-012, that evaluated safety in 192 patients with recurrent
or metastatic HNSCC and ECOG PS of zero or one; efficacy was
evaluated in 174 of these patients who had disease progression on
or after platinum-containing chemotherapy administered for
recurrent or metastatic HNSCC or following platinum-containing
chemotherapy administered as part of induction, concurrent, or
adjuvant therapy. Patients were enrolled regardless of tumor HPV
status (33% were HPV-positive). The median number of prior lines of
therapy administered for the treatment of HNSCC was two. Nearly all
(95%) of the patients enrolled had prior radiation therapy.
Patients received KEYTRUDA (pembrolizumab) at a dose of 10 mg/kg
every two weeks (n=53) or a 200 mg fixed dose every three weeks
(n=121) until unacceptable toxicity or disease progression.
Patients without disease progression were treated for up to 24
months. Treatment with KEYTRUDA could be reinitiated for subsequent
disease progression and administered for up to one additional year.
The primary efficacy outcome measures were ORR according to
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as
assessed by blinded independent central review (BICR), and duration
of response.
Efficacy analysis showed an ORR of 16 percent (95% CI: 11, 22)
with a complete response rate of five percent. The median follow-up
time was 8.9 months. Among the 28 responding patients, the
median duration of response had not been reached (range 2.4+ to
27.7+ months), with 23 patients having responses of six months
or longer. The ORR and duration of response were similar
irrespective of dosage regimen (10 mg/kg every 2 weeks or 200
mg every 3 weeks) or HPV status.
In HNSCC, serious adverse reactions occurred in 45 percent of
patients receiving KEYTRUDA. The most frequent serious adverse
reactions reported in at least two percent of patients were
pneumonia, dyspnea, confusional state, vomiting, pleural effusion,
and respiratory failure. The incidence of adverse reactions,
including serious adverse reactions, was similar between dosage
regimens (10 mg/kg every 2 weeks or 200 mg every
3 weeks). The most common adverse reactions (reported in at
least 20% of patients) were fatigue (46%), decreased appetite
(22%), and dyspnea (20%). Adverse reactions in patients with HNSCC
were generally similar to those occurring in patients with melanoma
and non-small cell lung cancer (NSCLC), with the exception of
increased incidences of facial edema (10% all Grades; 2.1% Grades
3-4) and new or worsening hypothyroidism.
About KEYTRUDA® (pembrolizumab)
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 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.
Lung Cancer
KEYTRUDA is indicated for the treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors express
PD-L1 as determined by an FDA-approved test with disease
progression on or after platinum-containing chemotherapy, at a dose
of 2 mg/kg every three weeks. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA
(pembrolizumab). 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.
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 at a fixed dose of 200 mg every three weeks. 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.
Selected Important Safety Information for
KEYTRUDA® (pembrolizumab)
Immune-mediated pneumonitis, including fatal cases, occurred in
patients receiving KEYTRUDA. Monitor patients for signs and
symptoms of pneumonitis. Evaluate suspected pneumonitis with
radiographic imaging and administer corticosteroids for Grade 2 or
greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently
discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2
pneumonitis.
Immune-mediated colitis occurred in patients 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.
Immune-mediated hepatitis occurred in patients 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 patients receiving KEYTRUDA. 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.
New or worsening hypothyroidism occurred in 28 (14.6%) of 192
patients, including Grade 3 (0.5%) hypothyroidism. 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 replacement hormones for hypothyroidism and
manage hyperthyroidism with thionamides and beta-blockers as
appropriate. Withhold or discontinue KEYTRUDA (pembrolizumab) for
Grade 3 or 4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis,
occurred in patients receiving KEYTRUDA. Monitor patients for
hyperglycemia or other signs and symptoms of diabetes. Administer
insulin for type 1 diabetes, and withhold KEYTRUDA and administer
anti-hyperglycemics in patients with severe hyperglycemia.
Immune-mediated nephritis occurred in patients receiving
KEYTRUDA. 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.
Other clinically important immune-mediated adverse reactions can
occur. 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.
Severe and life-threatening infusion-related reactions have been
reported in 3 (0.1%) of 2117 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.
KEYTRUDA (pembrolizumab) was discontinued due to adverse
reactions in 17 percent of 192 patients. Serious adverse reactions
occurred in 45 percent of patients. The most frequent serious
adverse reactions reported in at least 2 percent 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 (46%),
decreased appetite (22%), and dyspnea (20%).
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 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
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.
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 300 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 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 125 years, 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
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 2015
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
Patient Information/Medication Guide for KEYTRUDA
at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
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