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. 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.

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.

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.

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 treatments 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-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%).

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.

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.

ILD = interstitial lung disease.

Before prescribing
KEYTRUDA^® (pembrolizumab), please read the
Prescribing Information. The Medication Guide
also is available.

Reference: 1. FDA approves enfortumab vedotin-ejfv
with pembrolizumab for locally advanced or metastatic
urothelial cancer. U.S. Food and Drug Administration.
Updated December 15, 2023. Accessed February 5,
2024. https://www.fda.gov/drugs/resources-information-
approved-drugs/fda-approves-enfortumab-vedotin-
ejfv-pembrolizumab-locally-advanced-or-metastatic-
urothelial-cancer