KEYTRUDA Now Approved for First-Line
Treatment of Patients with Metastatic or with Unresectable,
Recurrent Head and Neck Squamous Cell Carcinoma as Monotherapy for
Patients Whose Tumors Express PD-L1 (CPS ≥1) or in Combination with
Platinum and Fluorouracil (FU) Regardless of PD-L1
Expression
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced that the U.S. Food and Drug Administration
(FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, as
monotherapy in patients whose tumors express PD-L1 (Combined
Positive Score [CPS] ≥1) or in combination with platinum and
fluorouracil (FU), a commonly used chemotherapy regimen, for the
first-line treatment of patients with metastatic or with
unresectable, recurrent head and neck squamous cell carcinoma
(HNSCC). The approval is based on results from the pivotal Phase 3
KEYNOTE-048 trial, where KEYTRUDA demonstrated a significant
improvement in overall survival (OS) compared with the EXTREME
regimen (cetuximab with carboplatin or cisplatin plus FU), a
standard treatment, as monotherapy in patients whose tumors
expressed PD-L1 (CPS ≥1) (HR=0.78 [95% CI, 0.64-0.96]; p=0.0171)
and in combination with chemotherapy in the total study population
(HR=0.77 [95% CI, 0.63-0.93]; p=0.0067). With these new
indications, KEYTRUDA is the first anti-PD-1 therapy approved in
the first-line setting as monotherapy in patients whose tumors
express PD-L1 (CPS ≥1) or in combination with chemotherapy
regardless of PD-L1 expression for patients with metastatic or with
unresectable, recurrent HNSCC and the first anti-PD-1 therapy to
demonstrate a statistically significant improvement in OS in these
patients.
“This approval is a very exciting milestone in the treatment of
head and neck cancer and has the potential to transform the way we
treat patients with this debilitating disease by offering important
new therapeutic options,” said Dr. Barbara Burtness, professor of
medicine, Yale School of Medicine and co-director, Development
Therapeutics Research Program, Yale Cancer Center. “Metastatic or
recurrent head and neck cancer has been an area of significant
unmet need, so it is encouraging to have immunotherapy regimens
available for patients in the first-line setting.”
Immune-mediated adverse reactions, which may be severe or fatal,
can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis,
endocrinopathies, nephritis and renal dysfunction, severe skin
reactions, solid organ transplant rejection, and complications of
allogeneic hematopoietic stem cell transplantation (HSCT). Based on
the severity of the adverse reaction, KEYTRUDA should be withheld
or discontinued and corticosteroids administered if appropriate.
KEYTRUDA can also cause severe or life-threatening infusion-related
reactions. Based on its mechanism of action, KEYTRUDA can cause
fetal harm when administered to a pregnant woman. For more
information, see “Selected Important Safety Information” below.
“Head and neck squamous cell carcinoma has historically
presented many challenges to physicians and patients, including
limited treatment options and physical and functional issues caused
by the disease and its treatment,” said Dr. Jonathan Cheng, vice
president, clinical research, Merck Research Laboratories. “This
approval is an important advance in the management of this
devastating cancer. The results of KEYNOTE-048, which support this
approval, demonstrated that KEYTRUDA monotherapy for patients whose
tumors expressed PD-L1 CPS greater than or equal to one and
KEYTRUDA in combination with chemotherapy regardless of PD-L1
expression significantly prolonged survival for patients with
metastatic or with unresectable, recurrent head and neck squamous
cell carcinoma in the first-line setting.”
KEYTRUDA was initially approved for the treatment of patients
with recurrent or metastatic HNSCC with disease progression on or
after platinum-containing chemotherapy in 2016 under the FDA’s
accelerated approval process based on objective response rate data
from the Phase 1b KEYNOTE-012 trial. In accordance with the
accelerated approval process, continued approval was contingent
upon verification and description of clinical benefit, which has
now been demonstrated in KEYNOTE-048 and has resulted in the FDA
converting the accelerated approval to a full (regular)
approval.
Data Supporting the Approval
This approval is based on data from the pre-specified interim
analysis of the Phase 3 KEYNOTE-048 trial, a randomized,
multi-center, open-label, active-controlled trial conducted in 882
patients with metastatic HNSCC who had not previously received
systemic therapy and who were considered incurable by local
therapies. Randomization was stratified by tumor PD-L1 expression
(Tumor Proportion Score [TPS] ≥50% or <50%) according to the
PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC
(positive or negative), and ECOG Performance Status (PS) (0 vs. 1).
Patients were randomized 1:1:1 to one of the following treatment
arms:
- KEYTRUDA 200 mg intravenously every
three weeks;
- KEYTRUDA 200 mg intravenously every
three weeks, carboplatin AUC 5 mg/mL/min intravenously every three
weeks or cisplatin 100 mg/m2 intravenously every three weeks and FU
1000 mg/m2/day as a continuous intravenous infusion over 96 hours
every three weeks (maximum of six cycles of platinum and FU);
- Cetuximab 400 mg/m2 intravenously as
the initial dose then 250 mg/m2 intravenously once weekly,
carboplatin AUC 5 mg/mL/min intravenously every three weeks or
cisplatin 100 mg/m2 intravenously every three weeks and FU 1000
mg/m2/day as a continuous intravenous infusion over 96 hours every
three weeks (maximum of six cycles of platinum and FU).
Among the 882 patients, the study population characteristics
were: median age of 61 years (range, 20 to 94), 36% age 65 or
older; 83% male; 73% White, 20% Asian, and 2.4% Black; 61% had ECOG
PS of 1; and 79% were former or current smokers. Twenty-two percent
of patients’ tumors were HPV positive; 23% had PD-L1 TPS ≥50%; and
95% had stage IV disease (19% were stage IVA, 6% were stage IVB,
and 70% were stage IVC). Eighty-five percent of patients’ tumors
had PD-L1 expression of CPS ≥1, and 43% had CPS ≥20.
Treatment with KEYTRUDA continued until RECIST v1.1-defined
progression of disease as determined by the investigator,
unacceptable toxicity or a maximum of 24 months. A retrospective
re-classification of patients’ tumor PD-L1 status according to CPS
using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor
specimens used for randomization.
The main efficacy outcome measures were OS and progression-free
survival (PFS) as assessed by blinded independent central review
(BICR) according to RECIST v1.1 (modified to follow a maximum of 10
target lesions and a maximum of five target lesions per organ)
sequentially tested in the subgroup of patients with CPS ≥20, the
subgroup of patients with CPS ≥1 and the overall population.
Efficacy Results for KEYTRUDA as a Single Agent in
KEYNOTE-048 (CPS ≥1 and CPS ≥20)
Endpoint CPS ≥1
CPS ≥20 KEYTRUDA
200 mg every 3 weeks
n=257
Cetuximab
Platinum
FU
n=255
KEYTRUDA
200 mg every 3 weeks
n=133
Cetuximab
Platinum
FU
n=122
OS Number of events (%) 177 (69%)
206 (81%) 82 (62%) 95 (78%)
Median in months (95% CI) 12.3
(10.8, 14.9)
10.3 (9.0,11.5) 14.9
(11.6, 21.5)
10.7
(8.8, 12.8)
Hazard ratio* (95% CI) 0.78 (0.64, 0.96)
0.61 (0.45, 0.83) p-Value† 0.0171
0.0015
PFS Number of events (%) 225
(88%) 231 (91%) 113 (85%)
111 (91%) Median in months (95% CI) 3.2 (2.2, 3.4)
5.0 (4.8, 5.8) 3.4 (3.2, 3.8)
5.0 (4.8, 6.2) Hazard ratio ‡ (95% CI) 1.15
(0.95, 1.38) 0.99 (0.75, 1.29)
Objective Response
Rate ORR‡ (95% CI) 19%
(14.5, 24.4)
35%
(29.1, 41.1)
23%
(16.4, 31.4)
36%
(27.6, 45.3)
Complete response rate 5% 3%
8% 3% Partial response rate 14%
32% 16% 33%
Duration
of Response Median in months (range) 20.9
(1.5+, 34.8+)
4.5
(1.2+, 28.6+)
20.9
(2.7, 34.8+)
4.2
(1.2+, 22.3+)
* Based on the stratified Cox proportional hazard model
† Based on a stratified log-rank test
‡ Response: Best objective response as
confirmed complete response or partial response
Efficacy Results for KEYTRUDA plus Platinum/Fluorouracil in
KEYNOTE-048
Endpoint
KEYTRUDA
200 mg every 3 weeks
Platinum
FU
n=281
Cetuximab
Platinum
FU
n=278
OS Number (%) of patients with event 197 (70%)
223 (80%) Median in months (95% CI)
13.0
(10.9, 14.7)
10.7
(9.3, 11.7)
Hazard ratio* (95% CI) 0.77 (0.63, 0.93) p-Value†
0.0067
PFS Number of patients with event (%)
244 (87%) 253 (91%) Median in months
(95% CI) 4.9 (4.7, 6.0) 5.1 (4.9, 6.0)
Hazard ratio* (95% CI) 0.92 (0.77, 1.10) p-Value†
0.3394
Objective Response Rate ORR‡ (95% CI)
36%
(30.0, 41.5)
36%
(30.7, 42.3)
Complete response rate 6% 3% Partial
response rate 30% 33%
Duration of
Response Median in months (range) 6.7
(1.6+, 30.4+)
4.3
(1.2+, 27.9+)
* Based on the stratified Cox proportional hazard model
† Based on stratified log-rank test
‡ Response: Best objective response as
confirmed complete response or partial response
In KEYNOTE-048, the safety of KEYTRUDA, as a single agent and in
combination with platinum (cisplatin or carboplatin) and FU
chemotherapy, was investigated in patients with previously
untreated, recurrent or metastatic HNSCC. The median duration of
exposure to KEYTRUDA 200 mg every three weeks was 3.5 months
(range, 1 day to 24.2 months) in the KEYTRUDA single agent arm and
was 5.8 months (range, 3 days to 24.2 months) in the combination
arm.
KEYTRUDA was discontinued for adverse reactions in 12% of
patients in the KEYTRUDA single agent arm. The most common adverse
reactions resulting in permanent discontinuation of KEYTRUDA were
sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to
the interruption of KEYTRUDA occurred in 31% of patients; the most
common adverse reactions leading to the interruption of KEYTRUDA
(≥2%) were pneumonia (2.3%), pneumonitis (2.3%) and hyponatremia
(2%). The most common adverse reactions (≥20%) with KEYTRUDA as a
single agent were fatigue (33%), constipation (20%), and rash
(20%).
KEYTRUDA was discontinued for adverse reactions in 16% of
patients in the combination arm. The most common adverse reactions
resulting in permanent discontinuation of KEYTRUDA were pneumonia
(2.5%), pneumonitis (1.8%) and septic shock (1.4%). Adverse
reactions leading to the interruption of KEYTRUDA occurred in 45%
of patients; the most common adverse reactions leading to
interruption of KEYTRUDA (≥2%) were neutropenia (14%),
thrombocytopenia (10%), anemia (6%), pneumonia (4.7%) and febrile
neutropenia (2.9%). The most common adverse reactions (≥20%) with
KEYTRUDA in combination with platinum and FU were nausea (51%),
fatigue (49%), constipation (37%), vomiting (32%), mucosal
inflammation (31%), diarrhea (29%), decreased appetite (29%),
stomatitis (26%) and cough (22%).
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 NSCLC expressing PD-L1 [Tumor Proportion
Score (TPS) ≥1%] as determined by an FDA-approved test, with no
EGFR or ALK genomic tumor aberrations, and is:
- stage III where patients are not
candidates for surgical resection or definitive chemoradiation,
or
- metastatic.
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, in combination with platinum and fluorouracil (FU), is
indicated for the first-line treatment of patients with metastatic
or with unresectable, recurrent head and neck squamous cell
carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first line
treatment of patients with metastatic or unresectable, recurrent
HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1]
as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of
patients with recurrent or metastatic HNSCC with disease
progression on or after platinum-containing chemotherapy.
In HNSCC, the recommended dose of KEYTRUDA is 200 mg
administered as an intravenous infusion over 30 minutes every
3 weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy,
administer KEYTRUDA prior to chemotherapy when given on the same
day. Refer to the Prescribing Information for the chemotherapy
agents administered in combination with KEYTRUDA for recommended
dosing information, as appropriate.
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 [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
(RCC). In RCC, 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
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%). Pneumonitis occurred in 6%
(18/300) of HNSCC patients receiving KEYTRUDA as a single agent,
including Grades 3-5 in 1.6% of patients, and occurred in 5.4%
(15/276) of patients receiving KEYTRUDA in combination with
platinum and FU as first-line therapy for advanced disease,
including Grade 3-5 in 1.5% of patients.
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 (KEYTRUDA) and Hepatoxicity
(KEYTRUDA 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. With the combination of
KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and
increased AST (13%) were seen. Monitor liver enzymes before
initiation of and periodically throughout treatment. Consider more
frequent monitoring of liver enzymes as compared to when the drugs
are administered as single agents. 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 1185 patients with HNSCC (16%),
receiving KEYTRUDA, as a single agent or in combination with
platinum and FU, including Grade 3 (0.3%) hypothyroidism.
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 cHL,
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-048, KEYTRUDA monotherapy was discontinued due to
adverse events in 12% of 300 patients with HNSCC; the most common
adverse reactions leading to permanent discontinuation were sepsis
(1.7%) and pneumonia (1.3%). The most common adverse reactions
(≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination
with platinum (cisplatin or carboplatin) and FU chemotherapy,
KEYTRUDA was discontinued due to adverse reactions in 16% of 276
patients with HNSCC. The most common adverse reactions resulting in
permanent discontinuation of KEYTRUDA were pneumonia (2.5%),
pneumonitis (1.8%), and septic shock (1.4%). The most common
adverse reactions (≥20%) were nausea (51%), fatigue (49%),
constipation (37%), vomiting (32%), mucosal inflammation (31%),
diarrhea (29%), decreased appetite (29%), stomatitis (26%), and
cough (22%).
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%).
In 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 the Merck Access Program for KEYTRUDA
At Merck, we are committed to supporting accessibility to our
cancer medicines. Merck provides multiple programs to help
appropriate patients who are prescribed KEYTRUDA have access to our
anti-PD-1 therapy. The Merck Access Program provides reimbursement
support for patients receiving KEYTRUDA, including information to
help with out-of-pocket costs and co-pay assistance for eligible
patients. More information is available by calling 855-257-3932 or
visiting www.merckaccessprogram-keytruda.com.
About Merck’s Patient Support Program for KEYTRUDA
Merck is committed to helping provide patients and their
caregivers support throughout their treatment with KEYTRUDA. The
KEY+YOU Patient Support Program provides a range of resources and
support. For further information and to sign up, eligible patients
may call 85-KEYTRUDA (855-398-7832) or visit www.keytruda.com.
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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Media Contacts:Pamela Eisele(267) 305-3558Ayn Wisler(908)
740-5590Investor Contacts:Teri Loxam(908) 740-1986Michael
DeCarbo(908) 740-1807
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