Moderna and Merck Announce mRNA-4157 (V940) in Combination With KEYTRUDA® (pembrolizumab) Demonstrated a Statistically Significant and Clinically Meaningful Improvement in Distant Metastasis-Free Survival (DMFS) in Patients with High-Risk Stage III/IV Melanoma Following Complete Resection Versus KEYTRUDA

Save

June 5, 2023 8:00 am ET

mRNA-4157 (V940) in combination with KEYTRUDA reduced the risk of distant
metastasis or death by 65% (HR=0.347 [95% CI, 0.145-0.828]); one-sided p
value=0.0063) compared to KEYTRUDA alone

The DMFS results, a key secondary endpoint of the Phase 2b KEYNOTE-942
study, will be presented at the 2023 American Society of Clinical Oncology
(ASCO) Annual Meeting

Companies plan to initiate a Phase 3 study in the adjuvant setting in
patients with high-risk melanoma in 2023, and rapidly expand to additional
tumor types, including non-small cell lung cancer

CAMBRIDGE, M.A. & RAHWAY, N.J., June 5, 2023 – Moderna, Inc.
(Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA)
therapeutics and vaccines, and Merck (NYSE:MRK), known as MSD outside of the
United States and Canada, today announced distant metastasis-free survival
(DMFS) results from the Phase 2b randomized KEYNOTE-942/mRNA-4157-P201 study,
a clinical trial evaluating mRNA-4157 (V940), an investigational
individualized neoantigen therapy (INT), in combination with KEYTRUDA,
Merck’s anti-PD-1 therapy, in patients with resected high-risk melanoma
(stage III/IV). In the overall intention-to-treat (ITT) population, adjuvant
treatment with mRNA-4157 (V940) in combination with KEYTRUDA demonstrated
a statistically significant and clinically meaningful improvement in DMFS, a
key secondary endpoint of the study, compared with KEYTRUDA alone and reduced
the risk of developing distant metastasis or death by 65% (HR=0.347 [95% CI,
0.145-0.828]); one-sided p value=0.0063). The secondary endpoint of DMFS,
defined as the time from the first dose of KEYTRUDA until the date of first
distant recurrence or death from any cause, was pre-specified for statistical
testing following the positive primary endpoint of recurrence-free survival
(RFS). These late-breaking data are being presented for the first time today
at 5:00 p.m. ET during an oral abstract session at the 2023 American Society
of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA9503).

“We are excited to be sharing these
results with the oncology community and thrilled to see such an exceptional
result in distant melanoma recurrence or death. Patients who experience
metastases at distant sites typically have worse survival outcomes and a poor
prognosis, thus these results showing a reduction in the risk of distant
recurrence underscore the potential of neoantigen therapy,” said Kyle
Holen, M.D., Moderna’s Senior Vice President and Head of Development,
Therapeutics and Oncology. “These results add to the emerging picture of
how individualized neoantigen therapy may advance melanoma treatment and the
promise it may hold for other types of cancer. Together with Merck, we are
rapidly advancing our efforts to move this forward for patients.”

“Patients with stage III and IV
melanoma can be at high risk of having their cancer recur or metastasize to
other sites,” said Dr. Eric H. Rubin, senior vice president, global
clinical development, Merck Research Laboratories. “These new DMFS
results build upon the positive recurrence-free survival data previously
observed from this Phase 2b study, and we look forward to working with Moderna
to initiate a Phase 3 study in melanoma later this year.”

Based on data from
KEYNOTE-942/mRNA-4157-P201, the U.S. Food and Drug Administration and European
Medicines Agency granted Breakthrough Therapy Designation and the Priority
Medicines (PRIME) scheme, respectively, for mRNA-4157 (V940) in combination
with KEYTRUDA for the adjuvant treatment of patients with high-risk melanoma
following complete resection. The companies recently announced the first
presentation of the study’s primary endpoint, RFS, from the Phase 2
KEYNOTE-942/mRNA-4157-P201 trial in April 2023 at the American Association for
Cancer Research (AACR) Annual Meeting.

Adverse events reported with mRNA-4157
(V940) in KEYNOTE-942 were consistent with those previously observed in a
Phase 1 clinical trial. The safety profile of KEYTRUDA was consistent with
findings from previous studies. The number of patients reporting treatment
related Grade ≥ 3 adverse events were similar between the arms (25% vs 18%,
respectively). The most common adverse events of any grade attributed to
either mRNA-4157 (V940) or the combination of mRNA-4157 (V940) and KEYTRUDA
were fatigue (60.6%), injection site pain (55.8%) and chills (50.0%).

Exploratory Subgroup Analysis Evaluating Minimal Residual Disease by
ctDNA

Data from an exploratory subgroup analysis
of KEYNOTE-942/mRNA-4157-P201 (Abstract #LBA9515) evaluating minimal residual
disease (MRD) by circulating tumor DNA (ctDNA) as a biomarker of RFS in
resected high-risk melanoma patients treated with mRNA-4157 (V940) in
combination with KEYTRUDA were also presented. For ctDNA assessments, tumor
core biopsies and matched whole-blood samples were subjected to whole-exome
sequencing to identify patient-specific somatic variants. The personalized
amplicon-based next-generation sequencing assay from NeoGenomics
(RaDaR^®) was used to select up to 48 variants most suitable for
MRD detection and analysis of ctDNA in baseline plasma samples. The
ctDNA-evaluable population (n=125) across both study arms was representative
of the total ITT population (n=157). The majority of ctDNA-evaluable patients
were ctDNA-negative at baseline (88.0%, n=110/125), compared to ctDNA-positive
patients at baseline (12.0%, n=15/125). In ctDNA-negative patients at
baseline, RFS was higher with mRNA-4157 (V940) in combination with KEYTRUDA
(n=77) versus KEYTRUDA monotherapy (n=33), representing a 78% reduction in
recurrence or death (HR=0.225 [95% CI 0.095-0.531]). A similar trend was
observed for ctDNA-positive patients (n=13 for the combination arm; n=2 for
KEYTRUDA only) at baseline. However, the small sample size of the ctDNA
subgroups limits the interpretation of these results. The association between
MRD patterns and mRNA-4157 (V940) treatment effect will be further explored in
upcoming planned studies.

About mRNA-4157 (V940)

mRNA-4157 (V940) is a novel investigational
messenger ribonucleic acid (mRNA)-based individualized neoantigen therapy¹
consisting of a single synthetic mRNA coding for up to 34 neoantigens that is
designed and produced based on the unique mutational signature of the DNA
sequence of the patient’s tumor. Upon administration into the body, the
algorithmically derived and RNA-encoded neoantigen sequences are endogenously
translated and undergo natural cellular antigen processing and presentation, a
key step in adaptive immunity.

Individualized neoantigen therapies are
designed to prime the immune system so that a patient can generate an
antitumor response specific to their tumor mutation signature. mRNA-4157
(V940) is designed to stimulate an immune response by generating specific T
cell responses based on the unique mutational signature of a patient’s
tumor. KEYTRUDA is an immunotherapy that works by increasing the ability of
the body’s immune system to help detect and fight tumor cells. Based on
early clinical studies, combining mRNA-4157 (V940) with KEYTRUDA may
potentially provide an additive benefit and enhance T cell-mediated
destruction of tumor cells.

About KEYNOTE-942/mRNA-4157-P201 (NCT03897881)

KEYNOTE-942 is an ongoing randomized,
open-label Phase 2b trial that enrolled 157 patients with high-risk stage
III/IV melanoma. Following complete surgical resection, patients were
randomized 2:1 (stratified by stage) to receive mRNA-4157 (V940) (1 mg every
three weeks for nine doses) and KEYTRUDA (200 mg every three weeks up to 18
cycles [for approximately one year]) versus KEYTRUDA alone for approximately
one year until disease recurrence or unacceptable toxicity. The primary
endpoint is RFS, defined as the time from first dose of KEYTRUDA until the
date of first recurrence (local, regional, or distant metastasis), a new
primary melanoma, or death from any cause in the intention-to-treat
population. Secondary endpoints include DMFS and safety, and exploratory
endpoints include distribution of TMB expression in baseline tumor samples
across study arms and their association with the primary RFS endpoint.

Key eligibility criteria for the trial
included: patients with resectable cutaneous melanoma metastatic to a lymph
node and at high risk of recurrence, patients with complete resection within
13 weeks prior to the first dose of KEYTRUDA, patients were disease free at
study entry (after surgery) with no loco-regional relapse or distant
metastasis and no clinical evidence of brain metastases, patients had a
formalin fixed paraffin embedded (FFPE) tumor sample available suitable for
sequencing, Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or
1 and patients with normal organ and marrow function reported at
screening.

About melanoma

Melanoma, the most serious form of skin
cancer, is characterized by the uncontrolled growth of pigment-producing
cells. The rates of melanoma have been rising over the past few decades, with
nearly 325,000 new cases diagnosed worldwide in 2020. In the U.S., skin cancer
is one of the most common types of cancer diagnosed, and melanoma accounts for
a large majority of skin cancer deaths. It is estimated there will be nearly
100,000 new cases of melanoma diagnosed and almost 8,000 deaths resulting from
the disease in the U.S. in 2023. The five-year survival rates are estimated to
be approximately 60.3% for stage III and 16.2% for stage IV.

About KEYTRUDA^® (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death
receptor-1 (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 1,600 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.

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the
treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant
treatment of adult and pediatric (12 years and older) patients with stage IIB,
IIC, or III melanoma following complete resection.

See additional selected indications for KEYTRUDA in the U.S. after the
Selected Important Safety Information

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody
that belongs to a class of drugs that bind to either the PD-1 or the PD-L1,
blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune
response, potentially breaking peripheral tolerance and inducing
immune-mediated adverse reactions. Immune-mediated adverse reactions, which
may be severe or fatal, can occur in any organ system or tissue, can affect
more than one body system simultaneously, and can occur at any time after
starting treatment or after discontinuation of treatment. Important
immune-mediated adverse reactions listed here may not include all possible
severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms
and signs that may be clinical manifestations of underlying immune-mediated
adverse reactions. Early identification and management are essential to ensure
safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes,
creatinine, and thyroid function at baseline and periodically during
treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant
setting, monitor blood cortisol at baseline, prior to surgery, and as
clinically indicated. In cases of suspected immune-mediated adverse reactions,
initiate appropriate workup to exclude alternative etiologies, including
infection. Institute medical management promptly, including specialty
consultation as appropriate.

Withhold or permanently discontinue
KEYTRUDA depending on severity of the immune-mediated adverse reaction. In
general, if KEYTRUDA requires interruption or discontinuation, administer
systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent)
until improvement to Grade 1 or less. Upon improvement to Grade 1 or less,
initiate corticosteroid taper and continue to taper over at least 1 month.
Consider administration of other systemic immunosuppressants in patients whose
adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated
pneumonitis. The incidence is higher in patients who have received prior
thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of
patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3
(0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required
in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of
KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients
who were withheld reinitiated KEYTRUDA after symptom improvement; of these,
23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of
adult patients with cHL receiving KEYTRUDA as a single agent, including Grades
3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a
median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates
were similar in patients with and without prior thoracic radiation.
Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of
the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68%
discontinued KEYTRUDA, and 77% had resolution.

Pneumonitis occurred in 41 (7%) patients,
including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. In
adult patients who received adjuvant therapy for NSCLC, patients received
high-dose corticosteroids for a median duration of 10 days (range: 1 day to
2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of
patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA,
63% discontinued KEYTRUDA, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis,
which may present with diarrhea. Cytomegalovirus infection/reactivation has
been reported in patients with corticosteroid-refractory immune-mediated
colitis. In cases of corticosteroid-refractory colitis, consider repeating
infectious workup to exclude alternative etiologies. Immune-mediated colitis
occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4
(<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic
corticosteroids were required in 69% (33/48); additional immunosuppressant
therapy was required in 4.2% of patients. Colitis led to permanent
discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of
patients. All patients who were withheld reinitiated KEYTRUDA after symptom
improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48
patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated
hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients
receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2
(0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of
patients; additional immunosuppressant therapy was required in 11% of
patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6)
and withholding in 0.3% (9) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence.
Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can
cause hepatic toxicity. Monitor liver enzymes before initiation of and
periodically throughout treatment. Consider monitoring more frequently 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. With the combination of KEYTRUDA and axitinib,
Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased
aspartate aminotransferase (AST) (13%) were seen at a higher frequency
compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased
ALT received systemic corticosteroids. In patients with ALT ≥3 times upper
limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%.
Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or
axitinib (n=34) administered as a single agent or with both (n=55), recurrence
of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16
patients receiving axitinib, and 24 patients receiving both. All patients with
a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary
adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment,
including hormone replacement as clinically indicated. Withhold KEYTRUDA
depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of
patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and
Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77%
(17/22) of patients; of these, the majority remained on systemic
corticosteroids. Adrenal insufficiency led to permanent discontinuation of
KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients
who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated
hypophysitis. Hypophysitis can present with acute symptoms associated with
mass effect such as headache, photophobia, or visual field defects.
Hypophysitis can cause hypopituitarism. Initiate hormone replacement as
indicated. Withhold or permanently discontinue KEYTRUDA depending on severity.
Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA,
including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions.
Systemic corticosteroids were required in 94% (16/17) of patients; of these,
the majority remained on systemic corticosteroids. Hypophysitis led to
permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7)
of patients. All patients who were withheld reinitiated KEYTRUDA after symptom
improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid
disorders. Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for
hypothyroidism or institute medical management of hyperthyroidism as
clinically indicated. Withhold or permanently discontinue KEYTRUDA depending
on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving
KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was
withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799)
of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%).
It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and
withholding in 0.3% (7) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8%
(237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade
2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and
withholding in 0.5% (14) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement. The majority of patients with
hypothyroidism required long-term thyroid hormone replacement. The incidence
of new or worsening hypothyroidism was higher in 1185 patients with HNSCC,
occurring in 16% of patients receiving KEYTRUDA as a single agent or in
combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The
incidence of new or worsening hypothyroidism was higher in 389 adult patients
with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%)
and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening
hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in
11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment,
including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening
hypothyroidism was higher in 580 patients with resected NSCLC, occurring in
22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment
(KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic
Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes.
Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA
depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients
receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and
withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were
withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis
occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4
(<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic
corticosteroids were required in 89% (8/9) of patients. Nephritis led to
permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3)
of patients. All patients who were withheld reinitiated KEYTRUDA after symptom
improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9
patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis,
including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic
symptoms, and toxic epidermal necrolysis, has occurred with
anti–PD-1/PD-L1 treatments. Topical emollients and/or topical
corticosteroids may be adequate to treat mild to moderate nonexfoliative
rashes. Withhold or permanently discontinue KEYTRUDA depending on severity.
Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of
patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%)
reactions. Systemic corticosteroids were required in 40% (15/38) of patients.
These reactions led to permanent discontinuation in 0.1% (2) and withholding
of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld
reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence.
The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions
occurred at an incidence of <1% (unless otherwise noted) in patients who
received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1
treatments. Severe or fatal cases have been reported for some of these adverse
reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis;
Nervous System: Meningitis, encephalitis, myelitis and demyelination,
myasthenic syndrome/myasthenia gravis (including exacerbation),
Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy;
Ocular: Uveitis, iritis and other ocular inflammatory toxicities can
occur. Some cases can be associated with retinal detachment. Various grades of
visual impairment, including blindness, can occur. If uveitis occurs in
combination with other immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with
systemic steroids to reduce the risk of permanent vision loss;
Gastrointestinal: Pancreatitis, to include increases in serum amylase
and lipase levels, gastritis, duodenitis;
Musculoskeletal and Connective Tissue: Myositis/polymyositis,
rhabdomyolysis (and associated sequelae, including renal failure), arthritis
(1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism;
Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic
lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic
necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune
thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions,
including hypersensitivity and anaphylaxis, which have been reported in 0.2%
of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of
infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1
or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and
permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT)

Fatal and other serious complications can occur in patients who receive
allogeneic HSCT before or after anti–PD-1/PD-L1 treatments.
Transplant-related complications include hyperacute graft-versus-host disease
(GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced
intensity conditioning, and steroid-requiring febrile syndrome (without an
identified infectious cause). These complications may occur despite
intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic
HSCT. Follow patients closely for evidence of these complications and
intervene promptly. Consider the benefit vs risks of using
anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

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 an anti–PD-1/PD-L1 treatment 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, when KEYTRUDA was administered as a single agent to patients
with stage III melanoma, 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-716, when KEYTRUDA was
administered as a single agent to patients with stage IIB or IIC melanoma,
adverse reactions occurring in patients with stage IIB or IIC melanoma were
similar to those occurring in 1011 patients with stage III melanoma from
KEYNOTE-054.

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 with advanced NSCLC; 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%).

Adverse reactions observed in KEYNOTE-091 were generally similar to those
occurring in other patients with NSCLC receiving KEYTRUDA as a single agent,
with the exception of hypothyroidism (22%), hyperthyroidism (11%), and
pneumonitis (7%). Two fatal reactions of myocarditis occurred.

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-204, KEYTRUDA was discontinued due to adverse reactions in 14% of
148 patients with cHL. Serious adverse reactions occurred in 30% of patients
receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia,
myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three
patients died from causes other than disease progression: 2 from complications
after allogeneic HSCT and 1 from unknown cause. The most common adverse
reactions (≥20%) were upper respiratory tract infection (41%),
musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and
cough (20% each).

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% were 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-869, when KEYTRUDA was administered in combination with enfortumab
vedotin to patients with locally advanced or mUC and who are not eligible for
cisplatin-based chemotherapy (n=121), fatal adverse reactions occurred in 5%
of patients, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia
gravis (0.8%), and pneumonitis (0.8%). Serious adverse reactions occurred in
50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the
serious adverse reactions in ≥2% of patients were acute kidney injury (7%),
urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia
(3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%),
hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary
retention (2.5%). Permanent discontinuation of KEYTRUDA occurred in 32% of
patients. The most common adverse reactions (≥2%) resulting in permanent
discontinuation of KEYTRUDA were pneumonitis (5%), peripheral neuropathy (5%),
rash (3.3%), and myasthenia gravis (2.5%). The most common adverse reactions
(≥20%) occurring in patients treated with KEYTRUDA in combination with
enfortumab vedotin were rash (71%), peripheral neuropathy (65%), fatigue
(60%), alopecia (52%), weight loss (48%), diarrhea (45%), pruritus (40%),
decreased appetite (38%), nausea (36%), dysgeusia (35%), urinary tract
infection (30%), constipation (27%), peripheral edema (26%), dry eye (25%),
dizziness (23%), arthralgia (23%), and dry skin (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of
370 patients with locally advanced or mUC. 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 mUC. The most common adverse reaction
resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%).
Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those
≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The
most common adverse reactions (≥20%) in patients who received KEYTRUDA were
fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite
(21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of
148 patients with high-risk NMIBC. The most common adverse reaction resulting
in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious
adverse reactions occurred in 28% of patients; those ≥2% were pneumonia
(3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis
(2%), and urinary tract infection (2%). The most common adverse reactions
(≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to
those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a
monotherapy.

In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with
MSI-H or dMMR cancer were similar to those occurring in patients with other
solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-811, when KEYTRUDA was administered in combination with
trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA
was discontinued due to adverse reactions in 6% of 217 patients with locally
advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The
most common adverse reaction resulting in permanent discontinuation was
pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference
of ≥5% incidence between patients treated with KEYTRUDA versus standard of
care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (reported in ≥20%) in patients receiving
KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea,
constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea,
pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis,
headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil
to patients with metastatic or locally advanced esophageal or GEJ (tumors with
epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates
for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued
due to adverse reactions in 15% of 370 patients. The most common adverse
reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were
pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most
common adverse reactions (≥20%) with KEYTRUDA in combination with
chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%),
constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and
weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received
KEYTRUDA as a monotherapy were similar to those occurring in patients with
melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel
and cisplatin or paclitaxel and carboplatin, with or without bevacizumab
(n=307), to patients with persistent, recurrent, or first-line metastatic
cervical cancer regardless of tumor PD-L1 expression who had not been treated
with chemotherapy except when used concurrently as a radio-sensitizing agent,
fatal adverse reactions occurred in 4.6% of patients, including 3 cases of
hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each
of acute myocardial infarction, autoimmune encephalitis, cardiac arrest,
cerebrovascular accident, femur fracture with perioperative pulmonary embolus,
intestinal perforation, and pelvic infection. Serious adverse reactions
occurred in 50% of patients receiving KEYTRUDA in combination with
chemotherapy with or without bevacizumab; those ≥3% were febrile
neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute
kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The
most common adverse reaction resulting in permanent discontinuation (≥1%)
was colitis (1%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the
most common adverse reactions (≥20%) were peripheral neuropathy (62%),
alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia
(41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each),
constipation and arthralgia (31% each), vomiting (30%), urinary tract
infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and
decreased appetite (21%).

For patients treated with KEYTRUDA in combination with chemotherapy with or
without bevacizumab, the most common adverse reactions (≥20%) were
peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%),
diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%),
hypertension and urinary tract infection (24% each), and rash (22%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98
patients with previously treated 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 (≥1%) were
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 were hepatotoxicity (13%),
diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular
accident (1.2%). 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%).

In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the
adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred
in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%)
were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and
diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2%
including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse
reactions occurred in 21% of 488 patients; the most common (≥1%) were
increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most
common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue
(40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).

Adverse reactions occurring in patients with MSI-H or dMMR endometrial
carcinoma who received KEYTRUDA as a single agent were similar to those
occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single
agent.

Adverse reactions occurring in patients with TMB-H cancer were similar to
those occurring in patients with other solid tumors who received KEYTRUDA as a
single agent.

Adverse reactions occurring in patients with recurrent or metastatic cSCC or
locally advanced cSCC were similar to those occurring in patients with
melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy
(carboplatin and paclitaxel followed by doxorubicin or epirubicin and
cyclophosphamide) followed by surgery and continued adjuvant treatment with
KEYTRUDA as a single agent (n=778) to patients with newly diagnosed,
previously untreated, high-risk early-stage TNBC, fatal adverse reactions
occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune
encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and
sepsis in association with multiple organ dysfunction syndrome and myocardial
infarction. Serious adverse reactions occurred in 44% of patients receiving
KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia
(2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients
due to adverse reactions. The most common reactions (≥1%) resulting in
permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and
rash (1%). The most common adverse reactions (≥20%) in patients receiving
KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%),
constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis
(34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough
(26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and
myalgia (20%).

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel
protein-bound, or gemcitabine and carboplatin) were administered to patients
with locally recurrent unresectable or metastatic TNBC who had not been
previously treated with chemotherapy in the metastatic setting (n=596), fatal
adverse reactions occurred in 2.5% of patients, including cardio-respiratory
arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in
30% of patients receiving KEYTRUDA in combination with chemotherapy; the
serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and
thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to
adverse reactions. The most common reactions resulting in permanent
discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and
pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients
receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea
(44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash
(26% each), cough (23%), decreased appetite (21%), and headache (20%).

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
last dose.

Pediatric Use

In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to
younger than 12 years and 108 pediatric patients aged 12 years to 17 years)
were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of
exposure was 2.1 months (range: 1 day to 25 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients
when compared to adults were pyrexia (33%), leukopenia (31%), vomiting (29%),
neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia
(22%), anemia (17%), decreased lymphocyte count (13%), and decreased white
blood cell count (11%).

Additional Indications for KEYTRUDA in the U.S.

Non-Small Cell 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.

KEYTRUDA, as a single agent, is indicated as adjuvant treatment following
resection and platinum-based chemotherapy for adult patients with stage IB
(T2a ≥4 cm), II, or IIIA NSCLC.

Head and Neck Squamous Cell 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 with 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.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or
refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory
cHL, or cHL that has relapsed after 2 or more lines of therapy.

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. KEYTRUDA is not recommended
for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the
treatment of adult patients with locally advanced or metastatic urothelial
carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response
rate and durability of response. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in the
confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with
locally advanced or metastatic urothelial carcinoma (mUC):

who are not eligible for any platinum-containing chemotherapy, or
who have disease progression during or following platinum-containing
chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with
Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive
bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary
tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient 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, as determined by an FDA-approved test,
that have progressed following prior treatment and who have no satisfactory
alternative treatment options.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal
Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an
FDA-approved test.

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and
platinum-containing chemotherapy, is indicated for the first-line treatment of
patients with locally advanced unresectable or metastatic HER2-positive
gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or
metastatic esophageal or gastroesophageal junction (GEJ) (tumors with
epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to
surgical resection or definitive chemoradiation either:

in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for
patients with tumors of squamous cell histology that express PD-L1 (CPS
≥10) as determined by an FDA-approved test.

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is
indicated for the treatment of patients with persistent, recurrent, or
metastatic cervical cancer whose tumors express PD-L1 (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 cervical cancer with disease progression on or after
chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an
FDA-approved test.

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.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with
recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line
treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at
intermediate-high or high risk of recurrence following nephrectomy, or
following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

KEYTRUDA, as a single agent, is indicated for the treatment of patients with
advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an
FDA-approved test, who have disease progression following prior systemic
therapy in any setting and are not candidates for curative surgery or
radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with
unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10
mutations/megabase] solid tumors, as determined by an FDA-approved test, that
have progressed following prior treatment and who have no satisfactory
alternative treatment options. 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 TMB-H central nervous
system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC
that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage
triple-negative breast cancer (TNBC) in combination with chemotherapy as
neoadjuvant treatment, and then continued as a single agent as adjuvant
treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of
patients with locally recurrent unresectable or metastatic TNBC whose tumors
express PD-L1 (CPS ≥10) as determined by an FDA-approved test.

Merck’s focus on cancer

Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck, the potential to
bring new hope to people with cancer drives our purpose and supporting
accessibility to our cancer medicines is our commitment. As part of our focus
on cancer, Merck is committed to exploring the potential of immuno-oncology
with one of the largest development programs in the industry across more than
30 tumor types. We also continue to strengthen our portfolio through strategic
acquisitions and are prioritizing the development of several promising
oncology candidates with the potential to improve the treatment of advanced
cancers. For more information about our oncology clinical trials, visit
www.merck.com/clinicaltrials.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified
around our purpose: We use the power of leading-edge science to save and
improve lives around the world. For more than 130 years, we have brought hope
to humanity through the development of important medicines and vaccines. We
aspire to be the premier research-intensive biopharmaceutical company in the
world – and today, we are at the forefront of research to deliver
innovative health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive global
workforce and operate responsibly every day to enable a safe, sustainable and
healthy future for all people and communities. For more information,
visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

About Moderna

In over 10 years since its inception, Moderna has transformed from a
research-stage company advancing programs in the field of messenger RNA
(mRNA), to an enterprise with a diverse clinical portfolio of vaccines and
therapeutics across seven modalities, a broad intellectual property portfolio
and integrated manufacturing facilities that allow for rapid clinical and
commercial production at scale. Moderna maintains alliances with a broad range
of domestic and overseas government and commercial collaborators, which has
allowed for the pursuit of both groundbreaking science and rapid scaling of
manufacturing. Most recently, Moderna’s capabilities have come together
to allow the authorized use and approval of one of the earliest and most
effective vaccines against the COVID-19 pandemic.

Moderna’s mRNA platform builds on continuous advances in basic and
applied mRNA science, delivery technology and manufacturing, and has allowed
the development of therapeutics and vaccines for infectious diseases,
immuno-oncology, rare diseases, cardiovascular diseases and auto-immune
diseases. Moderna has been named a top biopharmaceutical employer by
Science for the past eight years. To learn more, visit
www.modernatx.com.

Moderna’s focus on cancer

At Moderna, we are delivering on the promise of mRNA science to create a new
generation of transformative medicines for patients. We are relentlessly
working to grow our cancer therapeutic modality by discovering mRNA medicines
that harness the body’s immune system to identify and kill cancer cells
in the same way the immune system identifies and targets infections. One
example of a promising oncology candidate is the creation of individualized,
mRNA-based cancer therapies. We also continue to strengthen our portfolio
through strategic collaborations that increase our potential to improve
treatment options for patients with cancer.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J.,
USA

This news release of Merck & Co., Inc., Rahway, 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 candidates that the candidates 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 the global outbreak of
novel coronavirus disease (COVID-19); 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 Annual Report on Form 10-K for the year ended December 31,
2022 and the company’s other filings with the Securities and Exchange
Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Moderna Forward-Looking Statements

This press release contains forward-looking statements within the meaning of
the Private Securities Litigation Reform Act of 1995, as amended, including
regarding: the development by Moderna and Merck of an individualized
neoantigen therapy (mRNA-4157 (V940)); plans to initiate a Phase 3 study in
the adjuvant setting in patients with high-risk melanoma in 2023 and to
rapidly expand to additional tumor types, including non-small cell lung
cancer; the ability and potential for mRNA-4157 (V940) to improve distant
metastasis-free survival (DMFS) patients with high-risk stage III/IV melanoma;
the tolerability and safety profile for mRNA-4157 (V940); the potential for
mRNA, including mRNA-4157, to effectively treat different types of cancer; the
potential development of individualized, mRNA-based cancer therapies; the
ability of an individualized neoantigen therapy to trigger a tailored
antitumor response specific to a patient’s tumor mutation signature; and
the potential for expedited regulatory approval and commercialization of
mRNA-4157 (V940). The forward-looking statements in this press release are
neither promises nor guarantees, and you should not place undue reliance on
these forward-looking statements because they involve known and unknown risks,
uncertainties, and other factors, many of which are beyond Moderna’s control
and which could cause actual results to differ materially from those expressed
or implied by these forward-looking statements. These risks, uncertainties,
and other factors include those other risks and uncertainties described under
the heading “Risk Factors” in Moderna’s most recent Annual Report on Form 10-K
for the year ended December 31, 2022, filed with the U.S. Securities and
Exchange Commission (SEC) and in subsequent filings made by Moderna with the
SEC, which are available on the SEC’s website at www.sec.gov. Except as
required by law, Moderna disclaims any intention or responsibility for
updating or revising any forward-looking statements contained in this press
release in the event of new information, future developments or otherwise.
These forward-looking statements are based on Moderna’s current expectations
and speak only as of the date of this press release.