FDA Approves Two New Indications for Merck’s KEYTRUDA® (pembrolizumab)

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June 11, 2019 5:45 am ET

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

KENILWORTH, N.J.–(BUSINESS WIRE)–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/m²intravenously 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
Endpoint	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
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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

.