Survival Benefit Observed with KEYTRUDA
Monotherapy in Patients Whose Tumors Expressed PD-L1
with CPS≥20 and CPS≥1 and in Total Patient Population for
KEYTRUDA in Combination with Chemotherapy
KEYTRUDA is the First Anti-PD-1 Therapy to
Demonstrate a Survival Benefit as First-Line Therapy for Head and
Neck Cancer that has Recurred or Metastasized
Results from Pivotal Phase 3 KEYNOTE-048
Trial Presented Today at the ESMO 2018 Congress during the
Presidential Symposium
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced the first presentation of interim data from
the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA,
Merck’s anti-PD-1 therapy, as both monotherapy and in combination
with chemotherapy, for the first-line treatment of recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC). These
interim results are being presented today during the Presidential
Symposium at the ESMO 2018 Congress (Abstract # LBA8_PR) and are
included in the official Press Program.
Interim data from KEYNOTE-048 showed KEYTRUDA monotherapy
improved overall survival (OS), a primary endpoint of the study, by
39 percent (HR 0.61 [95% CI, 0.45-0.83]; p=0.0007) in patients
whose tumors expressed PD-L1 with Combined Positive Score (CPS)
≥20, and by 22 percent (HR 0.78 [95% CI, 0.64-0.96]; p=0.0086) in
patients with CPS≥1, compared to the EXTREME regimen (cetuximab
with carboplatin or cisplatin plus 5-fluorouracil (5-FU), the
current standard of care. In addition, KEYTRUDA in combination with
chemotherapy (carboplatin or cisplatin plus 5-FU) (KEYTRUDA
combination) demonstrated improved OS compared to the EXTREME
regimen by 23 percent (HR 0.77 [95% CI, 0.63-0.93]; p=0.0034),
regardless of PD-L1 expression. At the final analysis, superiority
for OS will be evaluated for KEYTRUDA monotherapy in the total
population and KEYTRUDA combination in patients whose tumors
express PD-L1 at CPS≥20 and CPS≥1; at this interim analysis,
based upon the prespecified testing algorithm, non-inferiority for
KEYTRUDA monotherapy in the total population was demonstrated and
statistical significance was not achieved for the KEYTRUDA
combination in the subset of patients whose tumors expressed PD-L1
at CPS ≥20 or ≥1. Additionally, at this time point there
was no difference in progression-free-survival (PFS), a dual
primary endpoint of the study, in any of the groups studied. There
were no new safety concerns identified with the use of KEYTRUDA in
KEYNOTE-048.
“In this study, KEYTRUDA showed the potential to significantly
prolong survival when used as first-line therapy for patients whose
head and neck cancer had recurred or spread,” said Dr. Barbara
Burtness, lead investigator for KEYNOTE-048, professor of medicine
at Yale School of Medicine and co-director, Development
Therapeutics Research Program, Yale Cancer Center. ”This is a
devastating cancer when it recurs, and there has not been any
advance in first-line treatment for over a decade. It is thrilling
to see these new data, which have the potential to alter the
standard of care in the first-line treatment of head and neck
cancer.”
“KEYTRUDA is the first anti-PD-1 therapy to show superior
overall survival as first-line treatment compared to the EXTREME
regimen, the current standard of care in patients with recurrent or
metastatic head and neck cancer,” said Dr. Roy Baynes, senior vice
president and head of Global Clinical Development, chief medical
officer, Merck Research Laboratories. “Recurrent or metastatic head
and neck cancer is a very challenging disease. Merck would like to
thank the patients and investigators for participating in this
important study, which is helping to advance our understanding of
the potential for KEYTRUDA and PD-1 inhibition in the first-line
setting.”
KEYTRUDA is currently approved in 61 countries for the treatment
of second-line recurrent or metastatic HNSCC, including the U.S.
and Europe. Merck plans to file a supplemental Biologics License
Application (sBLA) with the U.S. Food and Drug Administration (FDA)
for a first-line indication based on KEYNOTE-048 data and will
include data from the Phase 3 KEYNOTE-040 trial as supportive data.
Based on these results, Merck has withdrawn the sBLA for
KEYNOTE-040 for KEYTRUDA as a second-line treatment in patients
with recurrent or metastatic HNSCC, which was previously assigned a
Prescription Drug User Fee Act (PDUFA) or target action date of
Dec. 28, 2018. The results from KEYNOTE-048 will also be submitted
to regulatory authorities worldwide.
Study Design and Additional Data from KEYNOTE-048 (Abstract
# LBA8_PR)
KEYNOTE-048, a randomized, open-label Phase 3 trial
(ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA monotherapy
or KEYTRUDA combination, compared with the EXTREME regimen, as
first-line treatment in 882 patients with recurrent or metastatic
HSNCC. The dual primary endpoints were OS and PFS. The secondary
endpoints were PFS (at 6 months and 12 months), objective response
rate (ORR) and time to deterioration in Quality of Life Global
Health Status/Quality of Life Scales of the European Organization
for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire and Safety. Duration of response (DOR) was evaluated
as part of a pre-specified exploratory analysis. The primary and
secondary endpoints, as well as exploratory DOR analysis, were
evaluated in patients whose tumors expressed PD-L1 with CPS ≥20 and
CPS ≥1, and in the total population, regardless of PD-L1
expression, based on a fixed sequential testing strategy. At the
time of the analysis, the median follow-up was 11.7 months for
KEYTRUDA monotherapy, 13.0 months for KEYTRUDA combination and 10.7
months for the EXTREME regimen, respectively.
In the first comparison group, OS in the CPS ≥20 population was
significantly longer with KEYTRUDA monotherapy (14.9 months)
(n=133) compared to the EXTREME regimen (10.7 months) (n=122) (HR
0.61 [95% CI, 0.45-0.83]; p=0.0007). There was no difference in PFS
between the study arms (HR 0.99 [95% CI, 0.75-1.29]; p=0.5). ORR
was 23.3 percent for KEYTRUDA monotherapy and 36.1 percent for the
EXTREME regimen, respectively. The median DOR was substantially
longer with KEYTRUDA monotherapy (20.9 months) compared to the
EXTREME regimen (4.2 months).
Similarly, OS in the CPS ≥1 population was significantly longer
with KEYTRUDA monotherapy (12.3 months) (n=257) compared to the
EXTREME regimen (10.3 months) (n=255) (HR 0.78 [95% CI, 0.64-0.96];
p=0.0086). There was no difference in PFS between the study arms
(HR 1.16 [95% CI, 0.96-1.39]). ORR was 19.1 percent for KEYTRUDA
monotherapy and 34.9 percent for the EXTREME regimen, respectively.
The median DOR was substantially longer with KEYTRUDA (20.9 months)
compared to the EXTREME regimen (4.5 months).
In the second comparison group, OS in the total population was
significantly longer with the KEYTRUDA combination (13.0 months)
(n=281) compared to the EXTREME regimen (10.7 months) (n=278) (HR
0.77 [95% CI, 0.63-0.93]; p=0.0034). There was no difference in PFS
between the study arms (HR 0.92; 95% CI, 0.77-1.10). ORR was 35.6
percent for the KEYTRUDA combination and 36.3 percent for the
EXTREME regimen, respectively. The median DOR was longer with
KEYTRUDA combination (6.7 months) compared to the EXTREME regimen
(4.3 months).
There were no new safety concerns identified with the use of
KEYTRUDA in KEYNOTE-048. Grade 3-5 treatment-related adverse events
(TRAEs) occurred in 16.7 percent, 71.0 percent and 69.0 percent
(n=198/287) of patients in the KEYTRUDA monotherapy, KEYTRUDA
combination and the EXTREME regimen arms, respectively. TRAEs
resulting in discontinuation occurred in 4.7 percent, 22.8 percent
and 19.9 percent of patients in the KEYTRUDA monotherapy, KEYTRUDA
combination and the EXTREME regimen arms, respectively. There were
no TRAEs observed with an incidence of ≥15% in the KEYTRUDA
monotherapy arm. The most common TRAEs (occurring in ≥15% of
patients) in the KEYTRUDA combination arm included anemia (48.2%),
nausea (44.9%), neutropenia (33.0%), fatigue (30.4%), mucosal
inflammation (27.9%), thrombocytopenia (27.2%), vomiting (27.2%),
stomatitis (24.3%), decreased appetite (22.5%), platelet count
decreased (18.5%), diarrhea (17.8%) and neutrophil count decreased
(16.7%).
Immune-mediated adverse events in patients receiving KEYTRUDA
monotherapy or combination therapy were hypothyroidism (18.0% and
15.2%, respectively), pneumonitis (6.0% and 5.4%, respectively),
hyperthyroidism (2.7% and 4.7%, respectively), severe skin
reactions (2.7% and 0.7%, respectively), infusion reactions (1.3%
and 2.2%, respectively), colitis (1.0% and 2.5%, respectively),
nephritis (0.7% in both arms), pancreatitis (0.7% and 0.4%,
respectively), hypophysitis (0.3% and 0.4%, respectively);
hepatitis (0.7% monotherapy only); myocarditis and thyroiditis
(0.4% each, combination only); and adrenal insufficiency,
encephalitis and uveitis (0.3% each, monotherapy only).
Treatment-related deaths occurred in 3 patients in the KEYTRUDA
monotherapy arm [auto-inflammatory disease, disseminated
intravascular coagulation, and pneumonitis (n=1 each)]; 10 patients
in the KEYTRUDA combination arm [septic shock (n=5), cerebral
ischemia, hemorrhage, interstitial lung disease, sepsis, and tumor
hemorrhage (n=1 each)]; and 8 patients in the EXTREME regimen arm
[pneumonia (n=3), sepsis (n=2), and hypoxia, osteomyelitis, and
pulmonary artery thrombosis (n=1 each)].
Additional Information About KEYNOTE-048
KEYNOTE-048 enrolled 882 patients with recurrent or metastatic
HSNCC who were randomized to one of three regimens as first-line
therapy, as follows:
- KEYTRUDA monotherapy (200 mg fixed
dosed every three weeks [Q3W]) for up to 24 months (n=301); or
- KEYTRUDA (200 mg fixed dose Q3W) in
combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5
IV Q3W) plus 5-FU (1000 mg/m2/day IV continuous from Day 1-4 Q3W
(maximum six cycles), followed by additional KEYTRUDA monotherapy
maintenance therapy until progression of disease, toxicity or until
the patient had received a maximum of 24 months total treatment
(n=281); or
- EXTREME regimen including cetuximab at
a loading dose (400 mg/m2 IV) followed by weekly doses (250 mg/m2
IV) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin
(AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day
1-4 Q3W (maximum six cycles), followed by additional cetuximab
monotherapy maintenance therapy until progression of disease or
toxicity (n=300).
About Head and Neck Cancer
Head and neck cancer describes a number of different tumors that
develop in or around the throat, larynx, nose, sinuses and mouth.
Most head and neck cancers are squamous cell carcinomas that begin
in the flat, squamous cells that make up the thin surface layer of
the structures in the head and neck. The leading modifiable risk
factors for head and neck cancer include tobacco and heavy alcohol
use. Other risk factors include infection with certain types of
HPV, also called human papillomaviruses. Worldwide, an estimated
835,000 new head and neck cancer cases will be diagnosed in 2018,
and an estimated 431,000 people will die from the disease this
year. In the U.S., there were an estimated 63,000 new cases
diagnosed in 2017.
About KEYTRUDA® (pembrolizumab) Injection
100mg
KEYTRUDA is an anti-PD-1 therapy that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA is a humanized monoclonal antibody that 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.
Merck has the industry’s largest immuno-oncology clinical
research program. There are currently more than 850 trials studying
KEYTRUDA across a wide variety of cancers and treatment settings.
The KEYTRUDA clinical program seeks to understand the role of
KEYTRUDA across cancers and the factors that may predict a
patient’s likelihood of benefitting from treatment with KEYTRUDA,
including exploring several different biomarkers.
KEYTRUDA® (pembrolizumab) Indications and
Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with
unresectable or metastatic melanoma at a fixed dose of 200 mg every
three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of patients
with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic
tumor aberrations.
KEYTRUDA, as a single agent, 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, as a single agent, 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.
When administering KEYTRUDA in combination with chemotherapy,
KEYTRUDA should be administered prior to chemotherapy when given on
the same day. See also the Prescribing Information for pemetrexed
and carboplatin or cisplatin, as appropriate.
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.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with refractory primary mediastinal large B-cell lymphoma
(PMBCL), or who have relapsed after 2 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 confirmatory trials.
KEYTRUDA is not recommended for the treatment of patients with
PMBCL who require urgent cytoreductive therapy.
In adults with PMBCL, 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. In pediatric patients with PMBCL, 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.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally
advanced or metastatic urothelial carcinoma (mUC) who are not
eligible for cisplatin-containing chemotherapy and whose tumors
express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by
an FDA-approved test, or in patients who are not eligible for any
platinum-containing chemotherapy regardless of PD-L1 status. This
indication is approved under accelerated approval based on tumor
response rate and duration of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials.
KEYTRUDA is also indicated for the treatment of patients with
locally advanced or metastatic urothelial carcinoma (mUC) who have
disease progression during or following platinum-containing
chemotherapy or within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, 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.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with unresectable or metastatic microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR)
- solid tumors that have progressed
following prior treatment and who have no satisfactory alternative
treatment options, or
- colorectal cancer that has progressed
following treatment with fluoropyrimidine, oxaliplatin, and
irinotecan.
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. The
safety and effectiveness of KEYTRUDA in pediatric patients with
MSI-H central nervous system cancers have not been established.
In adult patients with MSI-H cancer, 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. In children with MSI-H cancer, 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.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma whose tumors express
PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an
FDA-approved test, with disease progression on or after two or more
prior lines of therapy including fluoropyrimidine- and
platinum-containing chemotherapy and if appropriate,
HER2/neu-targeted 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. The recommended dose of KEYTRUDA is a fixed
dose of 200 mg every three weeks until disease progression,
unacceptable toxicity, or up to 24 months in patients without
disease progression.
Cervical Cancer
KEYTRUDA is indicated for the treatment of patients with
recurrent or metastatic cervical cancer with disease progression on
or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as
determined by an FDA-approved test. 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. The recommended dose of KEYTRUDA is a
fixed dose of 200 mg every three weeks until disease progression,
unacceptable toxicity or up to 24 months in patients without
disease progression.
Selected Important Safety Information for KEYTRUDA
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving
KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%),
and 5 (0.1%), 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
for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in
1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2
(0.4%), 3 (1.1%), and 4 (<0.1%). 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 for Grade 4 colitis.
Immune-Mediated Hepatitis
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred
in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.4%), and 4 (<0.1%). 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.
Immune-Mediated Endocrinopathies
KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1
diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of
patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%).
Hypothyroidism occurred in 8.5% (237/2799) of patients, including
Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening
hypothyroidism was higher in patients with HNSCC occurring in 15%
(28/192) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of
patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis
occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%).
Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred
in 0.2% (6/2799) of patients.
Monitor patients for signs and symptoms of hypophysitis
(including hypopituitarism and adrenal insufficiency), thyroid
function (prior to and periodically during treatment), and
hyperglycemia. For hypophysitis, administer corticosteroids and
hormone replacement as clinically indicated. Withhold KEYTRUDA for
Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis.
Administer hormone replacement for hypothyroidism and manage
hyperthyroidism with thionamides and beta-blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.
Administer insulin for type 1 diabetes, and withhold KEYTRUDA and
administer antihyperglycemics in patients with severe
hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred
in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2
(0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in
1.7% (7/405) of patients receiving KEYTRUDA in combination with
pemetrexed and platinum chemotherapy. Monitor patients for changes
in renal function. Administer corticosteroids for Grade 2 or
greater nephritis. Withhold KEYTRUDA for Grade 2; permanently
discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
Immune-mediated rashes, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN) (some cases with fatal
outcome), exfoliative dermatitis, and bullous pemphigoid, can
occur. Monitor patients for suspected severe skin reactions and
based on the severity of the adverse reaction, withhold or
permanently discontinue KEYTRUDA and administer corticosteroids.
For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer
the patient for specialized care for assessment and treatment. If
SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions, which may be severe or fatal,
can occur in any organ system or tissue in patients receiving
KEYTRUDA and may also occur after discontinuation of treatment. 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%), uveitis, myositis, Guillain-Barré
syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic
anemia, sarcoidosis, and encephalitis. In addition, myelitis and
myocarditis were reported in other clinical trials and
postmarketing use.
Treatment with KEYTRUDA may increase the risk of rejection in
solid organ transplant recipients. Consider the benefit of
treatment vs the risk of possible organ rejection in these
patients.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related
reactions, including hypersensitivity and anaphylaxis, which have
been reported in 0.2% (6/2799) of patients. Monitor patients for
signs and symptoms of infusion-related reactions. For Grade 3 or 4
reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell
Transplantation (HSCT)
Immune-mediated complications, including fatal events, occurred
in patients who underwent allogeneic HSCT after treatment with
KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT
after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (1
fatal case) and 2 developed severe hepatic veno-occlusive disease
(VOD) after reduced-intensity conditioning (1 fatal case). 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. Follow patients closely for early
evidence of transplant-related complications such as hyperacute
graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD,
steroid-requiring febrile syndrome, hepatic veno-occlusive disease
(VOD), and other immune-mediated adverse reactions.
In patients with a history of allogeneic HSCT, acute GVHD
(including fatal GVHD) has been reported after treatment with
KEYTRUDA. Patients who experienced GVHD after their transplant
procedure may be at increased risk for GVHD after KEYTRUDA.
Consider the benefit of KEYTRUDA vs the risk of GVHD in these
patients.
Increased Mortality in Patients with Multiple Myeloma
In clinical trials in patients with multiple myeloma, the
addition of KEYTRUDA to a thalidomide analogue plus dexamethasone
resulted in increased mortality. Treatment of these patients with a
PD-1 or PD-L1 blocking antibody in this combination is not
recommended outside of controlled clinical trials.
Embryofetal Toxicity
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.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse
reactions in 9% of 555 patients with advanced melanoma; adverse
reactions leading to permanent 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%).
The most common adverse reactions (≥20%) with KEYTRUDA were fatigue
(28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed
and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA
was discontinued due to adverse reactions in 20% of 405 patients.
The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney
injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA
were nausea (56%), fatigue (56%), constipation (35%), diarrhea
(31%), decreased appetite (28%), rash (25%), vomiting (24%), cough
(21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-010, KEYTRUDA monotherapy 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%). The most common adverse reactions
(≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%),
and nausea (20%).
In KEYNOTE-012, 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 (≥20%)
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 and new or worsening
hypothyroidism.
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse
reactions in 5% of 210 patients with cHL. Serious adverse reactions
occurred in 16% of patients; those ≥1% included pneumonia,
pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two
patients died from causes other than disease progression; 1 from
GVHD after subsequent allogeneic HSCT and 1 from septic shock. The
most common adverse reactions (≥20%) were fatigue (26%), pyrexia
(24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and
rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse
reactions in 8% of 53 patients with PMBCL. Serious adverse
reactions occurred in 26% of patients and included arrhythmia (4%),
cardiac tamponade (2%), myocardial infarction (2%), pericardial
effusion (2%), and pericarditis (2%). Six (11%) patients died
within 30 days of start of treatment. The most common adverse
reactions (≥20%) were musculoskeletal pain (30%), upper respiratory
tract infection and pyrexia (28% each), cough (26%), fatigue (23%),
and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse
reactions in 11% of 370 patients with locally advanced or
metastatic urothelial carcinoma. Serious adverse reactions occurred
in 42% of patients; those ≥2% were urinary tract infection,
hematuria, acute kidney injury, pneumonia, and urosepsis. The most
common adverse reactions (≥20%) were fatigue (38%), musculoskeletal
pain (24%), decreased appetite (22%), constipation (21%), rash
(21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse
reactions in 8% of 266 patients with locally advanced or metastatic
urothelial carcinoma. The most common adverse reaction resulting in
permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated
patients; those ≥2% were urinary tract infection, pneumonia,
anemia, and pneumonitis. The most common adverse reactions (≥20%)
in patients who received KEYTRUDA were fatigue (38%),
musculoskeletal pain (32%), pruritus (23%), decreased appetite
(21%), nausea (21%), and rash (20%).
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse
reactions in 8% of 98 patients with recurrent or metastatic
cervical cancer. Serious adverse reactions occurred in 39% of
patients receiving KEYTRUDA; the most frequent included anemia
(7%), fistula, hemorrhage, and infections [except urinary tract
infections] (4.1% each). The most common adverse reactions (≥20%)
were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%),
pain and abdominal pain (22% each), and decreased appetite
(21%).
Lactation
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.
Pediatric Use
There is limited experience in pediatric patients. In a study in
40 pediatric patients with advanced melanoma, lymphoma, or
PD-L1–positive advanced, relapsed, or refractory solid tumors, the
safety profile 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%).
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology 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 more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases.
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. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us on Twitter,
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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 2017
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 at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
and
Medication Guide for KEYTRUDA at
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20181022005244/en/
MerckMediaPamela Eisele, 267-305-3558orElizabeth H. Sell,
267-305-3877orInvestorsTeri Loxam, 908-740-1986orMichael DeCarbo,
908-740-1807
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