Only Anti-PD-1 Therapy Approved for the
Treatment of Patients with Difficult-to-Treat cHL Regardless of
Prior Stem Cell Transplantation or Use of Brentuximab
Vedotin
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, for the treatment
of adult and pediatric patients with refractory classical Hodgkin
lymphoma (cHL), or who have relapsed after three or more prior
lines of therapy. Under the FDA’s accelerated approval regulations,
this indication 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. In refractory or relapsed cHL, KEYTRUDA
is approved for use in adult patients at a fixed dose of 200 mg and
in pediatric patients at a dose of 2 mg/kg (up to a maximum of 200
mg). KEYTRUDA is administered intravenously every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
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
when appropriate. Immune-mediated complications, including fatal
events, occurred in patients with cHL who underwent allogeneic
hematopoietic stem cell transplantation (HSCT) after being treated
with KEYTRUDA. Follow patients closely for early evidence of
transplant-related complications, and intervene promptly. KEYTRUDA
can also cause severe or life-threatening infusion-related
reactions. Monitor patients for signs and symptoms of
infusion-related reactions; for Grade 3 or 4 reactions, stop
infusion and permanently discontinue KEYTRUDA (pembrolizumab).
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 and
infusion-related adverse reactions and use in pregnancy, see
“Selected Important Safety Information” below.
The approval is based on data in 210 patients from the
KEYNOTE-087 trial, which demonstrated an overall response rate
(ORR) with KEYTRUDA (200 mg every three weeks) of 69 percent (95%
CI: 62, 75) with a complete remission rate (CRR) of 22 percent and
a partial remission rate (PRR) of 47 percent. The median follow-up
time was 9.4 months. Among the 145 responding patients, the
median duration of response was 11.1 months (range 0.0+ to 11.1
months).
“The results from KEYNOTE-087 showed that most patients with
relapsed or refractory classical Hodgkin lymphoma responded to
treatment with KEYTRUDA, and 22 percent experienced complete
remission,” said Dr. Roger M. Perlmutter, president, Merck Research
Laboratories. “Today’s approval – the first for KEYTRUDA in a
hematologic malignancy – reinforces the hope that immunotherapy
will prove useful in a wide variety of cancers.”
“For the patients with classical Hodgkin lymphoma who are not
cured with existing treatments, there are limited options, and
treating their disease becomes more challenging,” said Dr. Craig
Moskowitz, clinical director, division of hematologic oncology,
Memorial Sloan Kettering Cancer Center. “This approval is an
important step forward in treating these patients, who are
generally young and have a particularly poor prognosis, and gives
us the opportunity to help patients in their fight against this
devastating disease.”
Data Supporting the Approval
The accelerated FDA approval was based on data in 210 patients
with relapsed or refractory cHL enrolled in the multicenter,
nonrandomized, open-label KEYNOTE-087 study. Patients with active,
non-infectious pneumonitis, an allogeneic HSCT within the past five
years (or greater than five years but with symptoms of GVHD
[graft-versus-host disease]), active autoimmune disease, a medical
condition that required immunosuppression, or an active infection
requiring systemic therapy were ineligible for the trial. Patients
received KEYTRUDA at a dose of 200 mg every three weeks until
unacceptable toxicity or documented disease progression, or for up
to 24 months in patients who did not progress. The major efficacy
outcome measures (ORR, CRR, and duration of response) were assessed
by blinded independent central review according to the 2007 revised
International Working Group (IWG) criteria. Fifty-eight percent
(58%) of patients were refractory to the last prior therapy,
including 35 percent with primary refractory disease and 14 percent
whose disease was chemo-refractory to all prior regimens.
Additionally, 61 percent of patients had undergone prior auto-HSCT,
17 percent had no prior brentuximab use, and 36 percent had prior
radiation therapy.
Efficacy analysis showed an ORR of 69 percent (95% CI: 62, 75)
with a CRR of 22 percent and a PRR of 47 percent. The median
follow-up time was 9.4 months. Among the 145 responding
patients, the median duration of response was 11.1 months (range
0.0+ to 11.1 months).
KEYTRUDA (pembrolizumab) was discontinued due to adverse
reactions in five percent of 210 patients with cHL and treatment
was interrupted due to adverse reactions in 26 percent of patients.
Fifteen percent (15%) of patients had an adverse reaction requiring
systemic corticosteroid therapy. Serious adverse reactions occurred
in 16 percent of patients. The most frequent serious adverse
reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea,
GVHD, and herpes zoster. Two patients died from causes other than
disease progression; one from GVHD after subsequent allogeneic HSCT
and one from septic shock. The most common adverse reactions
(occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%),
cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash
(20%).
There is limited experience in pediatric patients. Efficacy for
pediatric patients was extrapolated from the results in the adult
cHL population. In a study of 40 pediatric patients with advanced
melanoma, PD-L1–positive advanced, relapsed, or refractory solid
tumors or lymphoma, patients were treated with KEYTRUDA for a
median of 43 days (range 1-414 days), with 24 patients (60%)
receiving treatment for 42 days or more. The safety profile in
pediatric patients was similar to that seen in adults treated with
KEYTRUDA. Toxicities that occurred at a higher rate (≥15%
difference) in these patients when compared to adults under 65
years of age were fatigue (45%), vomiting (38%), abdominal pain
(28%), hypertransaminasemia (28%), and hyponatremia (18%).
About KEYTRUDA® (pembrolizumab)
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.
KEYTRUDA (pembrolizumab) 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-dose 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 until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA is indicated for the first-line treatment of patients
with metastatic non-small cell lung cancer (NSCLC) whose tumors
have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as
determined by an FDA-approved test, with no EGFR or ALK genomic
tumor aberrations.
KEYTRUDA is also indicated for the treatment of patients with
metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined
by an FDA-approved test, with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of
200 mg every three weeks until disease progression, unacceptable
toxicity, or up to 24 months in patients without disease
progression.
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. 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. In HNSCC, KEYTRUDA (pembrolizumab) is
administered at a fixed dose of 200 mg every three weeks until
disease progression, unacceptable toxicity, or up to 24 months in
patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with refractory classical Hodgkin lymphoma (cHL), or who
have relapsed after three or more prior lines of therapy. 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. In adults with cHL,
KEYTRUDA is administered at a fixed dose of 200 mg every three
weeks until disease progression or unacceptable toxicity, or up to
24 months in patients without disease progression. In pediatric
patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg
(up to a maximum of 200 mg) every three weeks until disease
progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.
Selected Important Safety Information for
KEYTRUDA® (pembrolizumab)
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving
KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%),
and 5 (0.1%) pneumonitis, and occurred more frequently in patients
with a history of prior thoracic radiation (6.9%) compared to those
without (2.9%). 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 or recurrent Grade 2 pneumonitis.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in
48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 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 (pembrolizumab).
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17
(0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. 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.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96
(3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237
(8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2
(6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16
(0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.3%) thyroiditis. 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 for Grade 3 or 4 hyperthyroidism.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799
patients. Monitor patients for hyperglycemia or other signs and
symptoms of diabetes. Administer insulin for type 1 diabetes, and
withhold KEYTRUDA and administer antihyperglycemics in patients
with severe hyperglycemia.
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. 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.
KEYTRUDA can cause other clinically important immune-mediated
adverse reactions. 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
(pembrolizumab) 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.
The following clinically significant immune-mediated adverse
reactions occurred in less than 1% (unless otherwise indicated) of
2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous
pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, and partial seizures arising in a patient with inflammatory
foci in brain parenchyma. In addition, myelitis and myocarditis
were reported in other clinical trials, including cHL, and
postmarketing use.
Solid organ transplant rejection has been reported in
post-marketing use of KEYTRUDA. Treatment with KEYTRUDA may
increase the risk of rejection in solid organ transplant
recipients. Consider the benefit of treatment with KEYTRUDA versus
the risk of possible organ rejection in these patients.
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, which have been reported in 6 (0.2%) of 2799 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.
Immune-mediated complications, including fatal events, occurred
in patients who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after being treated with KEYTRUDA. Of 23
patients with cHL who proceeded to allogeneic HSCT after treatment
with KEYTRUDA on any trial, 6 patients (26%) developed GVHD, one of
which was fatal, and 2 patients (9%) developed severe hepatic
veno-occlusive disease (VOD) after reduced-intensity conditioning,
one of which was fatal. Cases of fatal hyperacute GVHD after
allogeneic HSCT have also been reported in patients with lymphoma
who received a PD-1 receptor-blocking antibody before
transplantation. These complications may occur despite intervening
therapy between PD-1 blockade and allogeneic HSCT. Follow patients
closely for early evidence of transplant-related complications such
as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
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
(pembrolizumab).
KEYTRUDA was discontinued due to adverse reactions in 5% of 210
patients with cHL and treatment was interrupted due to adverse
reactions in 26% of patients. Fifteen percent (15%) of patients had
an adverse reaction requiring systemic corticosteroid therapy.
Serious adverse reactions occurred in 16% of patients. The most
frequent serious adverse reactions (≥1%) included pneumonia,
pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two
patients died from causes other than disease progression; one from
GVHD after subsequent allogeneic HSCT and one from septic shock.
The most common adverse reactions (occurring in ≥20% of patients)
were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal
pain (21%), diarrhea (20%), and rash (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.
There is limited experience in pediatric patients. In a study of
40 pediatric patients with advanced melanoma, PD-L1–positive
advanced, relapsed, or refractory solid tumors or lymphoma,
patients were treated with KEYTRUDA for a median of 43 days (range
1-414 days), with 24 patients (60%) receiving treatment for 42 days
or more. The safety profile in pediatric patients was similar to
that seen in adults treated with KEYTRUDA. Toxicities that occurred
at a higher rate (≥15% difference) in these patients when compared
to adults under 65 years of age were fatigue (45%), vomiting (38%),
abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia
(18%).
Our Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
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 400 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 are 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 over a century, 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,
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Kenilworth, N.J., USA
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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
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There can be no guarantees with respect to pipeline products that
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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
Patient Information/Medication Guide for KEYTRUDA
at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
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