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