Survival Benefit Now Observed with KEYTRUDA
in Combination with Chemotherapy in All Patient Populations
(Regardless of PD-L1 Expression) and with KEYTRUDA Monotherapy in
Patients Whose Tumors Expressed PD-L1 at CPS ≥1
Data Presented Today at 2019 ASCO Annual
Meeting
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced the presentation of the final analysis of
the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA,
Merck’s anti-PD-1 therapy, as monotherapy and in combination with
chemotherapy, for the first-line treatment of patients with
recurrent or metastatic head and neck squamous cell carcinoma
(HNSCC) at the 2019 American Society of Clinical Oncology (ASCO)
Annual Meeting (Abstract #6000). Data include the first-time
presentation of certain overall survival (OS) hypotheses from the
KEYTRUDA in combination with chemotherapy study arm based on PD-L1
expression and the KEYTRUDA monotherapy study arm in the total
patient population. Results of an interim analysis were presented
at the European Society for Medical Oncology (ESMO) 2018 Congress
and demonstrated superior OS outcomes for KEYTRUDA in combination
with chemotherapy in the total population and KEYTRUDA monotherapy
in patients whose tumors expressed PD-L1 with Combined Positive
Score (CPS) ≥20 and CPS ≥1 compared with the EXTREME regimen, the
current standard of care.
“It is exciting to see the full results from this trial, which
is the first study to show superior overall survival over the
current standard of care known as the EXTREME regimen,” said Dr.
Danny Rischin, director of the department of medical oncology,
Peter MacCallum Cancer Centre, Melbourne, Australia. “Patients with
recurrent or metastatic head and neck cancer have a poor prognosis
with limited treatment options. These findings underscore the
potential of KEYTRUDA monotherapy and in combination with
platinum-based chemotherapy to become important new treatment
options.”
The new findings presented today from the final analysis showed
that KEYTRUDA in combination with chemotherapy (carboplatin or
cisplatin plus 5-FU) reduced the risk of death by 40% in patients
whose tumors expressed PD-L1 with CPS≥20, demonstrating
significantly longer OS (14.7 months [95% CI, 10.3-19.3]) compared
with the EXTREME regimen (cetuximab with carboplatin or cisplatin
plus 5-fluorouracil [5-FU]), the current standard of care (11.0
months [95% CI, 9.2-13.0]) (HR=0.60 [95% CI, 0.45-0.82]; p=0.0004).
For the dual primary endpoint of progression-free survival (PFS),
statistical significance was not achieved for KEYTRUDA in
combination with chemotherapy in the CPS≥20 population compared
with the EXTREME regimen (HR=0.73 [95% CI, 0.55-.97]; p=0.0162).
New findings for the CPS ≥1 population showed KEYTRUDA in
combination with chemotherapy reduced the risk of death by 35% in
these patients, with significantly longer OS (13.6 months [95% CI,
10.7-15.5]) compared with the EXTREME regimen (10.4 months [95% CI,
9.1-11.7]) (HR=0.65 [95% CI, 0.53-0.80]; p<0.0001). Per the
sequential testing strategy, superiority for PFS was not tested in
this population (HR=0.82 [95% CI, 0.67-1.00]). Results for OS with
KEYTRUDA monotherapy in the total population were consistent with
the previously presented interim analysis, where non-inferiority
was demonstrated (HR=0.83 [95% CI, 0.70-0.99]; p=0.0199), with a
median OS of 11.5 months (95% CI, 10.3-13.4) for KEYTRUDA
monotherapy in the total population compared with 10.7 months (95%
CI, 9.3-11.7) for the EXTREME regimen. There was no difference in
PFS between KEYTRUDA monotherapy in the total population and the
EXTREME regimen (HR=1.34 [95% CI, 1.13-1.59]).
“As a company, Merck is committed to advancing research in this
challenging treatment setting through our expansive head and neck
cancer clinical research program,” said Dr. Jonathan Cheng, vice
president, clinical research, Merck Research Laboratories. “The
full data from KEYNOTE-048 illustrate the impact of KEYTRUDA as
monotherapy and in combination with chemotherapy as potential new
first-line treatment options for patients with recurrent or
metastatic head and neck squamous cell carcinoma. We would like to
sincerely thank the patients and investigators for their
involvement in KEYNOTE-048.”
As previously announced, the U.S. Food and Drug Administration
(FDA) has granted priority review for a new supplemental Biologics
License Application (sBLA) seeking approval for KEYTRUDA as
monotherapy or in combination with platinum and 5-FU chemotherapy
for the first-line treatment of patients with recurrent or
metastatic HNSCC based in part on data from the second interim
analysis of KEYNOTE-048. The FDA has set a Prescription Drug User
Fee Act (PDUFA), or target action, date of June 10, 2019.
Study Design and Additional Data from KEYNOTE-048 (Abstract
#6000)
KEYNOTE-048, a randomized, open-label Phase 3 trial
(ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA in
combination with chemotherapy or KEYTRUDA monotherapy, compared
with the EXTREME regimen, as first-line treatment in patients with
recurrent or metastatic HNSCC. The dual primary endpoints were OS
and PFS. The secondary endpoints were PFS (at six months and 12
months), objective response rate (ORR) and time to deterioration in
the 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 (CPS ≥20 and CPS ≥1) and in the total population,
based on a fixed sequential testing strategy. Data cutoff for the
final analysis was Feb. 25, 2019; data cutoff for the previously
presented second interim analysis was June 13, 2018. Details of the
OS benefit observed at the final analysis are below:
Summary of Overall Survival
Population (number of patients with
event) Final Analysis Hazard Ratio (95% CI)
KEYTRUDA Monotherapy PD-L1 CPS ≥20 (n=133) vs. EXTREME (n=122)
0.58 (0.44-0.78)b PD-L1 CPS ≥1 (n=257) vs.
EXTREME (n=255) 0.74 (0.61-0.90)b Total
Population (n=301) vs. EXTREME (n=300) 0.83
(0.70-0.99); p=0.0199c
KEYTRUDA in Combination
withChemotherapy
PD-L1 CPS ≥20 (n=126) vs. EXTREME (n=110) 0.60
(0.45–0.82); p=0.0004a PD-L1 CPS ≥1 (n=242) vs. EXTREME (n=235)
0.65 (0.53–0.80); p<0.0001a Total
Population (n=281) vs. EXTREME (n=278) 0.72
(0.60-0.87)b a Superiority demonstrated. b No new
statistical testing performed because population previously
demonstrated superiority at interim analysis. c Superiority not
demonstrated.
The secondary endpoint of ORR was 42.9% for KEYTRUDA in
combination with chemotherapy in patients whose tumors expressed
PD-L1 with CPS ≥20 compared with 38.2% for the EXTREME regimen. The
ORR was 36.4% in patients whose tumors expressed PD-L1 with CPS ≥1
for KEYTRUDA in combination with chemotherapy compared with 35.7%
for the EXTREME regimen. The median DOR was 7.1 months (range, 2.1+
to 39.0+) for KEYTRUDA in combination with chemotherapy in patients
whose tumors expressed PD-L1 with CPS ≥20 compared with 4.2 months
(range, 1.2+ to 31.5+) for the EXTREME regimen. The median DOR was
6.7 months (range, 1.6+ to 39.0+) for KEYTRUDA in combination with
chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥1
compared with 4.3 months (range, 1.2+ to 31.5+) for the EXTREME
regimen.
In the KEYTRUDA monotherapy arm, an analysis of the total
patient population showed an ORR of 16.9% compared with 36.0% for
the EXTREME regimen; the median DOR was 22.6 months (range, 1.5+ to
43.0+) compared with 4.5 months (range, 1.2+ to 38.7+) for the
EXTREME regimen.
As previously reported, there were no new safety concerns
identified with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5
all-cause adverse events occurred in 54.7%, 85.1% and 83.3% of
patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with
chemotherapy and EXTREME regimen arms, respectively. Adverse events
resulting in discontinuation occurred in 12.0%, 32.6% and 27.5% of
patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with
chemotherapy and EXTREME regimen arms, respectively.
Treatment-related deaths occurred in 1.0%, 4.0% and 2.8% of
patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with
chemotherapy and EXTREME regimen arms, respectively. Grade 3-5
immune-mediated or infusion reactions occurred in 7.0%, 5.4% and
10.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in
combination with chemotherapy and EXTREME regimen arms,
respectively.
Additional Information About KEYNOTE-048
KEYNOTE-048 enrolled 882 patients with recurrent or metastatic
HNSCC 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. Two substances that greatly
increase the risk of developing head and neck cancer are tobacco
and alcohol. It is estimated that there were more than 887,000 new
cases of head and neck cancer diagnosed and over 453,000 deaths
from the disease worldwide in 2018. In the U.S. alone, it is
estimated that there will be more than 65,000 new cases of head and
neck cancer diagnosed and over 14,000 deaths from the disease in
2019.
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 1,000 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. The recommended dose of
KEYTRUDA in patients with unresectable or metastatic melanoma is
200 mg administered as an intravenous infusion over 30 minutes
every three weeks until disease progression or unacceptable
toxicity.
KEYTRUDA is indicated for the adjuvant treatment of patients
with melanoma with involvement of lymph node(s) following complete
resection. The recommended dose of KEYTRUDA for the adjuvant
treatment of adult patients with melanoma is 200 mg administered as
an intravenous infusion over 30 minutes every three weeks until
disease recurrence, unacceptable toxicity, or for up to 12 months
in patients without disease recurrence.
Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum
chemotherapy, is indicated for the first-line treatment of patients
with metastatic nonsquamous non-small cell lung cancer (NSCLC),
with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel
or paclitaxel protein-bound, is indicated for the first-line
treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line
treatment of patients with stage III NSCLC who are not candidates
for surgical resection or definitive chemoradiation, or metastatic
NSCLC, and whose tumors express PD-L1 [tumor proportion score (TPS)
≥1%] as determined by an FDA-approved test, with no EGFR or ALK
genomic tumor aberrations.
KEYTRUDA, as a single agent, is 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 NSCLC, the recommended dose of KEYTRUDA is 200 mg
administered as an intravenous infusion over 30 minutes 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 the
chemotherapy agents administered in combination with KEYTRUDA, 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 200 mg is administered as
an intravenous infusion over 30 minutes 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 3 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 200 mg is administered as an intravenous infusion over 30
minutes 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 as an intravenous infusion over 30 minutes 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 200 mg is administered as an
intravenous infusion over 30 minutes 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 as an intravenous infusion over 30
minutes 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 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
200 mg is administered as an intravenous infusion over 30 minutes
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 200 mg is
administered as an intravenous infusion over 30 minutes every three
weeks until disease progression, unacceptable toxicity, or up to 24
months in patients without disease progression. In pediatric
patients with MSI-H cancer, KEYTRUDA is administered as an
intravenous infusion over 30 minutes 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 (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 200 mg as an intravenous infusion over 30 minutes 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 200
mg as an intravenous infusion over 30 minutes every three weeks
until disease progression, unacceptable toxicity or up to 24 months
in patients without disease progression.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib. 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 200 mg as
an intravenous infusion over 30 minutes every three weeks until
disease progression, unacceptable toxicity, or up to 24 months in
patients without disease progression.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric
patients with recurrent locally advanced or metastatic Merkel cell
carcinoma. 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 in adults is 200 mg administered as an
intravenous infusion over 30 minutes every three weeks until
disease progression, unacceptable toxicity, or up to 24 months in
patients without disease progression. The recommended dose of
KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200
mg), administered as an intravenous infusion over 30 minutes every
three weeks until disease progression or unacceptable toxicity, or
up to 24 months in patients without disease progression.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the
first-line treatment of patients with advanced renal cell
carcinoma. In renal cell carcinoma, KEYTRUDA 200 mg is administered
as an intravenous infusion over 30 minutes every 3 weeks in
combination with 5 mg axitinib orally twice daily until disease
progression, unacceptable toxicity, or for KEYTRUDA, up to 24
months in patients without disease progression. When axitinib is
used in combination with KEYTRUDA, dose escalation of axitinib
above the initial 5 mg dose may be considered at intervals of six
weeks or longer. See also the Prescribing Information for
recommended axitinib dosing information.
Selected Important Safety Information for KEYTRUDA
(pembrolizumab) Injection, 100mg
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis, including fatal
cases. Pneumonitis occurred in 3.4% (94/2799) of patients with
various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2
(1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in
8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single
agent, including Grades 3-4 in 3.2% of patients, and occurred more
frequently in patients with a history of prior thoracic radiation
(17%) compared to those without (7.7%).
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.
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 KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis, or Hepatoxicity (in Combination
With Axitinib)
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.
Hepatotoxicity (in Combination With Axitinib)
KEYTRUDA in combination with axitinib can cause hepatic toxicity
with higher than expected frequencies of Grades 3 and 4 ALT and AST
elevations compared to KEYTRUDA alone. Grades 3 and 4 increased ALT
and AST were seen in 20% and 13% of patients, respectively. Monitor
liver enzymes before initiation of and periodically throughout
treatment. Consider more frequent monitoring of liver enzymes as
compared to when the drugs are used in monotherapy. For elevated
liver enzymes, interrupt KEYTRUDA and axitinib, and consider
administering corticosteroids as needed.
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, including
classical Hodgkin lymphoma, 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 (26%) developed graft-versus-host disease (GVHD)
(1 fatal case) and 2 (9%) 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 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 trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm
when administered to a pregnant woman. Advise women of this
potential risk. In females of reproductive potential, verify
pregnancy status prior to initiating KEYTRUDA and advise them to
use effective contraception during treatment and for 4 months after
the last dose.
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-054, KEYTRUDA was permanently discontinued due to
adverse reactions in 14% of 509 patients; the most common (≥1%)
were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious
adverse reactions occurred in 25% of patients receiving KEYTRUDA.
The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea
(28%).
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-407, when KEYTRUDA was administered with carboplatin
and either paclitaxel or paclitaxel protein-bound in metastatic
squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions
in 15% of 101 patients. The most frequent serious adverse reactions
reported in at least 2% of patients were febrile neutropenia,
pneumonia, and urinary tract infection. Adverse reactions observed
in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with
the exception that increased incidences of alopecia (47% vs 36%)
and peripheral neuropathy (31% vs 25%) were observed in the
KEYTRUDA and chemotherapy arm compared to the placebo and
chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse
reactions in 19% of 636 patients; the most common were pneumonitis
(3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The
most frequent serious adverse reactions reported in at least 2% of
patients were pneumonia (7%), pneumonitis (3.9%), pulmonary
embolism (2.4%), and pleural effusion (2.2%). The most common
adverse reaction (≥20%) was fatigue (25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to
adverse reactions in 8% of 682 patients with metastatic NSCLC; the
most common 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 who received KEYTRUDA
as a monotherapy, 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%).
Adverse reactions occurring in patients with gastric cancer were
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy.
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%).
Adverse reactions occurring in patients with HCC were generally
similar to those in patients with melanoma or NSCLC who received
KEYTRUDA as a monotherapy, with the exception of increased
incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis
(2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a
higher incidence were elevated AST (20%), ALT (9%), and
hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017,
adverse reactions occurring in patients with MCC were generally
similar to those occurring in patients with melanoma or NSCLC who
received KEYTRUDA as a monotherapy. Laboratory abnormalities
(Grades 3-4) that occurred at a higher incidence were elevated AST
(11%) and hyperglycemia (19%).
KEYNOTE-426, when KEYTRUDA was administered in combination with
axitinib, fatal adverse reactions occurred in 3.3% of 429 patients.
Serious adverse reactions occurred in 40% of patients, the most
frequent of which (≥1%) included hepatotoxicity (7%), diarrhea
(4.2%), acute kidney injury (2.3%), dehydration (1%), and
pneumonitis (1%).
Permanent discontinuation due to an adverse reaction occurred in
31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the
combination (8%). The most common adverse reactions (>1%)
resulting in permanent discontinuation of KEYTRUDA, axitinib, or
the combination were hepatotoxicity (13%), diarrhea/colitis (1.9%),
acute kidney injury (1.6%), and cerebrovascular accident
(1.2%).
When KEYTRUDA was used in combination with axitinib, the most
common adverse reactions (≥20%) were diarrhea (56%),
fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%),
hypothyroidism (35%), decreased appetite (30%), palmar-plantar
erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal
inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and
constipation (21%).
Lactation
Because of the potential for serious adverse reactions in
breastfed children, advise women not to breastfeed during treatment
and for 4 months after the final dose.
Pediatric Use
There is limited experience in pediatric patients. In a trial,
40 pediatric patients (16 children aged 2 years to younger than 12
years and 24 adolescents aged 12 years to 18 years) with various
cancers, including unapproved usages, were administered KEYTRUDA 2
mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3
doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses
or more. The safety profile in these pediatric patients was similar
to that seen in adults; adverse reactions 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%), increased transaminases (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,
Facebook, Instagram, 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 2018
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.
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740-1037
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