Moderna & Merck Announce 3-Year Data For mRNA-4157 (V940) in Combination With KEYTRUDA® (pembrolizumab) Demonstrated Sustained Improvement in Recurrence-Free Survival & Distant Metastasis-Free Survival Versus KEYTRUDA in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection

Save

June 3, 2024 8:00 am ET

At a median planned follow-up of the Phase 2b study at 34.9 months,
mRNA-4157 (V940) in combination with KEYTRUDA reduced the risk of recurrence
or death by 49% and the risk of distant metastasis or death by 62% compared
to KEYTRUDA alone in these patients

The 2.5-year recurrence-free survival rate of mRNA-4157 (V940) in
combination with KEYTRUDA was 74.8% as compared to 55.6% for KEYTRUDA alone,
with the benefit observed across exploratory subgroups

The companies have initiated Phase 3 studies in patients with high-risk
melanoma and non-small cell lung cancer, in addition to Phase 2 studies in
patients with renal cell carcinoma and urothelial carcinoma and a Phase 2/3
study for cutaneous squamous cell carcinoma

CAMBRIDGE, Mass. and RAHWAY, N.J., June 3, 2024 – Moderna, Inc. (NASDAQ: MRNA)
and Merck (NYSE: MRK), known as MSD outside of the United States and Canada,
today announced the first presentation of results from a planned analysis 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) following complete
resection (n=157). With a median follow-up of approximately three years (34.9
months), adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA
continued to demonstrate a clinically meaningful and durable improvement in
recurrence-free survival (RFS), the primary endpoint of the study, reducing
the risk of recurrence or death by 49% (HR [95% CI], 0.510 [0.288–0.906];
two-sided nominal p-value 0.019) compared with KEYTRUDA alone. mRNA-4157
(V940) in combination with KEYTRUDA also continued to demonstrate a meaningful
improvement in distant metastasis-free survival (DMFS), a key secondary
endpoint of the study, compared with KEYTRUDA alone, reducing the risk of
developing distant metastasis or death by 62% (HR [95% CI], 0.384
[0.172–0.858], two-sided nominal p-value 0.015).

These data are being presented today during a rapid oral abstract session at
the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract
#LBA9512). With an additional year of planned follow-up, these data build on
the earlier analysis of the primary
and key
secondary
endpoints
of the study, presented in 2023. The 2.5-year RFS rate of mRNA-4157 (V940) in
combination with KEYTRUDA was 74.8%, as compared to 55.6% for KEYTRUDA alone,
with the benefit observed across exploratory subgroups.

“We are encouraged by the latest results from the KEYNOTE-942/mRNA-4157-P201
study. These data highlight the sustained benefit in RFS and DMFS of mRNA-4157
(V940) as adjuvant treatment in combination with KEYTRUDA in people with
resected high-risk melanoma. Importantly, this benefit was observed across
various patient exploratory subgroups, reflecting the potential of mRNA-4157
(V940) for a broad range of these patients,” said Kyle Holen, M.D., Moderna’s
Senior Vice President and Head of Development, Therapeutics and Oncology.
“These findings reinforce our commitment to advancing this innovative
treatment in collaboration with Merck, and we are dedicated to harnessing mRNA
technology to potentially transform cancer therapy and improve patient
outcomes.”

“The sustained improvements in recurrence-free survival and distant
metastasis-free survival observed at approximately three years in the
KEYNOTE-942/mRNA-4157-P201 study provide further support of the potential of
mRNA-4157 (V940) in combination with KEYTRUDA to help patients with resected
high-risk melanoma,” said Dr. Marjorie Green, senior vice president and head
of oncology, global clinical development, Merck Research Laboratories. “We
look forward to building on our legacy of turning breakthrough science into
medicines that may have a meaningful impact on patients’ lives as we continue
advancing our broad clinical development program evaluating this novel
approach with Moderna.”

Additional efficacy and subgroup data

Data from an exploratory subgroup analysis of the Phase 2b
KEYNOTE-942/mRNA-4157-P201 study in patients with resected high-risk melanoma
(stage III/IV) following complete resection showed that improvement in RFS was
observed with mRNA-4157 (V940) in combination with KEYTRUDA compared to
KEYTRUDA alone regardless of tumor mutational burden (TMB) or programmed
death-ligand 1 (PD-L1) status.

The RFS benefit of mRNA-4157 (V940) in combination with KEYTRUDA compared to
KEYTRUDA alone was maintained across both TMB high (HR [95% CI], 0.564
[0.253–1.258]), TMB non-high (0.571 [0.245–1.331]), PD-L1 positive (0.471
[0.226–0.979]), PD-L1 negative (0.147 [0.034–0.630]), and circulating tumor
DNA (ctDNA) negative (0.207 [0.091–0.470]) subpopulations. ctDNA positive HR
was not estimable due to the small sample size. There were no significant
associations between individual human leukocyte antigen (HLA) alleles and RFS
observed for mRNA-4157 (V940) in combination with KEYTRUDA.

The exploratory endpoint of overall survival (OS) favored mRNA-4157 (V940) in
combination with KEYTRUDA compared to KEYTRUDA alone, with a 2.5-year OS rate
of 96.0% vs. 90.2%, respectively (HR [95% CI], 0.425 [0.114–1.584]).

The safety profile with mRNA-4157 (V940) in combination with KEYTRUDA in
KEYNOTE-942/mRNA-4157-P201 remains consistent with the primary analysis. The
most common adverse events attributed to mRNA-4157 (V940) in combination with
KEYTRUDA were fatigue (60.6%), injection site pain (56.7%), and chills
(49.0%). The majority of the adverse events attributed to mRNA-4157 (V940)
were Grade 1-2, with fatigue being the most common Grade 3 event and no Grade
4-5 events. Immune-related adverse events occurred in 37.5% of patients
receiving the combination and 36% receiving KEYTRUDA alone.

Ongoing clinical development programs

Merck and Moderna have initiated Phase 3 randomized clinical trials evaluating
mRNA-4157 (V940) in combination with KEYTRUDA as an adjuvant treatment in
patients with resected high-risk (Stage IIB-IV) melanoma (INTerpath-001,
NCT05933577) and non-small cell lung cancer
(INTerpath-002,
NCT06077760). Both trials
are actively enrolling.

In 2024, Merck and Moderna also initiated a two-part Phase 2/3 randomized
clinical trial evaluating mRNA-4157 (V940) in combination with KEYTRUDA as
neoadjuvant and adjuvant treatment in patients with resectable locally
advanced Stage II-IV (M0) cutaneous squamous cell carcinoma (INTerpath-007,
NCT06295809), a Phase 2 randomized clinical
trial evaluating mRNA-4157 (V940) in
combination with KEYTRUDA as adjuvant treatment in patients with
intermediate-high-risk, high-risk, or M1 no evidence of disease renal cell
carcinoma (INTerpath-004,
NCT06307431), and a Phase
2 randomized clinical trial evaluating mRNA-4157 (V940) in
combination with KEYTRUDA as adjuvant treatment in patients with high-risk
muscle-invasive urothelial carcinoma post-radical resection (INTerpath-005,
NCT06305767).

About mRNA-4157 (V940)

mRNA-4157 (V940) is a novel investigational messenger RNA (mRNA)-based
individualized neoantigen therapy (INT) consisting of a 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 train and activate an
antitumor 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. As previously
announced
from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial evaluating patients with
high-risk stage III/IV melanoma, combining mRNA-4157 (V940) with KEYTRUDA may
provide a meaningful benefit over KEYTRUDA alone.

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 assigned 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 distant
metastasis-free survival 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. The KEYNOTE-942 trial is
ongoing to collect additional translational data and an additional 100
patients are currently being enrolled.

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 more than 330,000 new cases
diagnosed worldwide in 2022. 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 more than 100,000 new
cases of melanoma diagnosed and more than 8,000 deaths resulting from the
disease in the U.S. in 2024.

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 KEYTRUDA indications 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 programmed death receptor-1 (PD-1) or the programmed death
ligand 1 (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 7% (41/580) of adult patients with resected NSCLC who
received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including
fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. 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, other
transplant (including corneal graft) 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%).

In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC
receiving KEYTRUDA in combination with platinum-containing chemotherapy, given
as neoadjuvant treatment and continued as single-agent adjuvant treatment,
were generally similar to those occurring in patients in other clinical trials
across tumor types receiving KEYTRUDA in combination with chemotherapy.

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, insomnia,
palmar-plantar erythrodysesthesia, urinary tract infection, and
hypothyroidism.

In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in
combination with platinum-containing chemotherapy as neoadjuvant treatment,
serious adverse reactions occurred in 34% of 396 patients. The most frequent
(≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism
(3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients,
including death due to unknown cause (0.8%), sepsis (0.3%), and
immune-mediated lung disease (0.3%). Permanent discontinuation of any study
drug due to an adverse reaction occurred in 18% of patients who received
KEYTRUDA in combination with platinum-containing chemotherapy; the most
frequent adverse reactions (≥1%) that led to permanent discontinuation of any
study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%),
anemia (1.5%), neutropenia (1.5%) and pneumonia (1.3%).

Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396
patients did not receive surgery due to adverse reactions. The most frequent
(≥1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm
was interstitial lung disease (1%).

In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a
single agent as adjuvant treatment, serious adverse reactions occurred in 14%
of 290 patients. The most frequent serious adverse reaction was pneumonia
(3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent
discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of
patients who received KEYTRUDA as a single agent, given as adjuvant treatment;
the most frequent adverse reactions (≥1%) that led to permanent
discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease
(1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain
(1%).

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 adverse 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-A39, when KEYTRUDA was administered in combination with enfortumab
vedotin to patients with locally advanced or metastatic urothelial cancer
(n=440), fatal adverse reactions occurred in 3.9% of patients, including acute
respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).
Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in
combination with enfortumab vedotin; the serious adverse reactions in ≥2% of
patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%),
urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia
(2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred
in 27% of patients. The most common adverse reactions (≥2%) resulting in
permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash
(3.4%). The most common adverse reactions (≥20%) occurring in patients treated
with KEYTRUDA in combination with enfortumab vedotin were rash (68%),
peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%),
alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%),
constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract
infection (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of
370 patients with locally advanced or metastatic urothelial carcinoma. Serious
adverse reactions occurred in 42% of patients; those ≥2% were urinary tract
infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most
common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain
(24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea
(20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of
266 patients with locally advanced or metastatic urothelial carcinoma. The
most common adverse reaction resulting in permanent discontinuation of
KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of
KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia,
anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients
who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus
(23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-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%).

In KEYNOTE-859, when KEYTRUDA was administered in combination with
fluoropyrimidine- and platinum-containing chemotherapy, serious adverse
reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of
patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and
vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who
received KEYTRUDA including infection (2.3%) and thromboembolism (1.3%).
KEYTRUDA was permanently discontinued due to adverse reactions in 15% of
patients. The most common adverse reactions resulting in permanent
discontinuation of KEYTRUDA (≥1%) were infections (1.8%) and diarrhea (1.0%).
The most common adverse reactions (reported in ≥20%) in patients receiving
KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%),
nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased
appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia
syndrome (25%), constipation (22%), and weight loss (20%).

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-A18, when KEYTRUDA was administered with CRT (cisplatin plus
external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to
patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions
occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large
intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious
adverse reactions occurred in 30% of patients; those ≥1% included urinary
tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was
discontinued for adverse reactions in 7% of patients. The most common adverse
reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). For
patients treated with KEYTRUDA in combination with CRT, the most common
adverse reactions (≥10%) were nausea (56%), diarrhea (50%), vomiting (33%),
urinary tract infection (32%), fatigue (26%), hypothyroidism (20%),
constipation (18%), decreased appetite and weight loss (17% each), abdominal
pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and
pelvic pain (10%).

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%).

In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of
299 patients with previously treated hepatocellular carcinoma. The most common
adverse reaction resulting in permanent discontinuation of KEYTRUDA was
ascites (2.3%). The most common adverse reactions in patients receiving
KEYTRUDA (≥10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased
appetite (15%), pruritus (12%), upper respiratory tract infection (11%), cough
(11%), and hypothyroidism (10%).

In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine
and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529
patients with locally advanced unresectable or metastatic biliary tract
cancer. The most common adverse reaction resulting in permanent
discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions
leading to the interruption of KEYTRUDA occurred in 55% of patients. The most
common adverse reactions or laboratory abnormalities leading to interruption
of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet
count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia
(3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased
AST (2.5%), and biliary obstruction (2.3%).

In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with
MCC (n=105) were generally similar to those occurring in patients with
melanoma or NSCLC who received KEYTRUDA as a single agent.

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%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased
white blood cell count (11%).

Geriatric Use

Of the 564 patients with locally advanced or metastatic urothelial cancer
treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were
65-74 years and 26% (n=144) were 75 years or older. No overall differences in
safety or effectiveness were observed between patients 65 years of age or
older and younger patients. Patients 75 years of age or older treated with
KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence
of fatal adverse reactions than younger patients. The incidence of fatal
adverse reactions was 4% in patients younger than 75 and 7% in patients 75
years or older.

Additional Selected KEYTRUDA Indications 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 is indicated for the treatment of patients with resectable (tumors ≥4
cm or node positive) NSCLC in combination with platinum-containing
chemotherapy as neoadjuvant treatment, and then continued as a single agent as
adjuvant treatment after surgery.

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 Cancer

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the
treatment of adult patients with locally advanced or metastatic urothelial
cancer.

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

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
adults with locally advanced unresectable or metastatic HER2-positive gastric
or gastroesophageal junction (GEJ) adenocarcinoma 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 of this indication may be
contingent upon verification and description of clinical benefit in the
confirmatory trials.

KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing
chemotherapy, is indicated for the first-line treatment of adults with locally
advanced unresectable or metastatic HER2-negative 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 chemoradiotherapy (CRT), is indicated for the
treatment of patients with FIGO 2014 Stage III-IVA 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) secondary to hepatitis B who have received prior systemic
therapy other than a PD-1/PD-L1-containing regimen.

Biliary Tract Cancer

KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the
treatment of patients with locally advanced unresectable or metastatic biliary
tract cancer (BTC).

Merkel Cell Carcinoma

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

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 (mut/Mb)] 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

Every day, we follow the science as we work to discover innovations that can
help patients, no matter what stage of cancer they have. As a leading oncology
company, we are pursuing research where scientific opportunity and medical
need converge, underpinned by our diverse pipeline of more than 25 novel
mechanisms. With one of the largest clinical development programs across more
than 30 tumor types, we strive to advance breakthrough science that will shape
the future of oncology. By addressing barriers to clinical trial
participation, screening and treatment, we work with urgency to reduce
disparities and help ensure patients have access to high-quality cancer care.
Our unwavering commitment is what will bring us closer to our goal of bringing
life to more patients with cancer. For more information, visit
https://www.merck.com/research/oncology/.

About Merck’s research in melanoma

Merck is committed to delivering meaningful advances for patients with
melanoma and to continuing research in skin cancers through a broad clinical
development program across investigational and approved medicines. KEYTRUDA
has been established as an important treatment option for the adjuvant
treatment of patients with resected Stage IIB, IIC, or III melanoma based on
results of KEYNOTE-054 and KEYNOTE-716. KEYTRUDA is also approved worldwide
for the treatment of patients with unresectable or metastatic melanoma.

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 
X (formerly Twitter),
Facebook,
Instagram,
YouTube and
LinkedIn.

About Moderna

Moderna is a leader in the creation of the field of mRNA medicine. Through the
advancement of mRNA technology, Moderna is reimagining how medicines are made
and transforming how we treat and prevent disease for everyone. By working at
the intersection of science, technology and health for more than a decade, the
company has developed medicines at unprecedented speed and efficiency,
including one of the earliest and most effective COVID-19 vaccines.

Moderna’s mRNA platform has enabled the development of therapeutics and
vaccines for infectious diseases, immuno-oncology, rare diseases and
autoimmune diseases. With a unique culture and a global team driven by the
Moderna values and mindsets to responsibly change the future of human health,
Moderna strives to deliver the greatest possible impact to people through mRNA
medicines. For more information about Moderna, please visit modernatx.com
and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and
LinkedIn.

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 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, 2023 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
statements regarding: the ability for mRNA-4157/V940 and KEYTRUDA to
demonstrate a clinically meaningful improvement in recurrence-free survival
and distant metastasis-free survival compared with KEYTRUDA alone, the
tolerability and safety profile for mRNA-4157/V940; the ability of an
individualized neoantigen therapy to trigger a tailored antitumor response
specific to a patient’s tumor mutation signature; and the conduct of
additional trials and plans for studying individualized neoantigen therapy in
additional types of cancer. 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, among others, those risks and
uncertainties described under the heading “Risk Factors” in Moderna’s Annual
Report on Form 10-K for the fiscal year ended December 31, 2023, 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.