European Medicines Agency’s CHMP Recommends Approval of Merck’s KEYTRUDA® (pembrolizumab) for the Treatment of Patients with Relapsed or Refractory Classical Hodgkin Lymphoma
March 24, 2017 8:13 am ET
Recommendation Is for Adult Patients Who Have Failed Autologous Stem Cell Transplant and Brentuximab Vedotin (BV), or Who Are Transplant-Ineligible and Have Failed BV
KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today 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 adult patients
with relapsed or refractory classical Hodgkin lymphoma (cHL) who
have failed autologous stem cell transplant (ASCT) and brentuximab
vedotin (BV), or who are transplant-ineligible and have failed BV. The
recommendation will now be reviewed by the European Commission for
marketing authorization in the European Union. A decision on approval is
expected in the second quarter of 2017.
“This CHMP positive recommendation brings us one step closer to offering
appropriate patients in the European Union with classical Hodgkin
lymphoma a new treatment option to help fight this hematologic cancer,”
said Dr. Roger Dansey, senior vice president and therapeutic area head,
oncology late-stage development, Merck Research Laboratories. “Today’s
news reflects Merck’s ongoing commitment to bring forward new options
for patients with a wide range of cancers.”
The positive opinion was based on data from the KEYNOTE-087 and
KEYNOTE-013 trials. These multicenter, open label trials evaluated
patients with cHL who failed ASCT and BV, who were ineligible for ASCT
because they were unable to achieve a complete or partial remission
after salvage chemotherapy and failed BV, or who failed ASCT and did not
Both studies included patients regardless of PD-L1 expression. The major
efficacy outcome measures, overall response rate and complete remission
rate, were assessed by blinded independent central review according to
the 2007 revised International Working Group (IWG) criteria. Secondary
efficacy outcome measures were duration of response, progression-free
survival and overall survival.
About Classical Hodgkin Lymphoma
Hodgkin lymphoma is a type of lymphoma that develops in the white blood
cells, called lymphocytes, which are part of the immune system. Hodgkin
lymphoma can start almost anywhere – most often in lymph nodes in the
upper part of the body, with the most common sites being in the chest,
neck or under the arms. Worldwide, there were approximately 66,000 new
cases of Hodgkin lymphoma and 25,500 people died from the disease in
2012. Classical Hodgkin lymphoma accounts for about 95 percent of all
cases of Hodgkin lymphoma in developed countries.
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 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 in the U.S.
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.
KEYTRUDA (pembrolizumab) 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
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 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
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
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. The incidence of new or worsening hypothyroidism
was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients
with HNSCC, including Grade 3 (0.5%) hypothyroidism. 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 (pembrolizumab) 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 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
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 (pembrolizumab).
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.
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9%
of 555 patients with advanced melanoma; adverse reactions leading to
discontinuation in more than one patient were colitis (1.4%), autoimmune
hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and
cardiac failure (0.4%). Adverse reactions leading to interruption of
KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea
(2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab
were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs
23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are
listed for ipilimumab only for those adverse reactions that occurred at
the same or lower rate than with KEYTRUDA.
In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in
12% of 357 patients with advanced melanoma; the most common (≥1%) were
general physical health deterioration (1%), asthenia (1%), dyspnea (1%),
pneumonitis (1%), and generalized edema (1%). Adverse reactions leading
to interruption of KEYTRUDA occurred in 14% of patients; the most common
(≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The
most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue
(43% with KEYTRUDA [pembrolizumab]), pruritus (28% vs 8%), rash (24% vs
8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea
(20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding
incidence rates are listed for chemotherapy only for those adverse
reactions that occurred at the same or lower rate than with KEYTRUDA.
KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients
with metastatic NSCLC. The most common adverse event resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse
reactions leading to interruption of KEYTRUDA occurred in 23% of
patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%),
pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite
(1.3%), and pneumonitis (1%). The most common adverse reactions
(occurring in at least 20% of patients and at a higher incidence than
with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs
20%), and nausea (20% vs 18%).
KEYTRUDA was discontinued due to adverse reactions in 17% of 192
patients with HNSCC. Serious adverse reactions occurred in 45% of
patients. The most frequent serious adverse reactions reported in at
least 2% 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,
decreased appetite, and dyspnea. Adverse reactions occurring in patients
with HNSCC were generally similar to those occurring in patients with
melanoma or NSCLC, with the exception of increased incidences of facial
edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening
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 (pembrolizumab) 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%).
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Please see Prescribing Information for KEYTRUDA (pembrolizumab) at
Information/Medication Guide for KEYTRUDA at
Pamela Eisele, 267-305-3558
Kim Hamilton, 908-740-1863
Teri Loxam, 908-740-1986
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