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
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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.
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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
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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
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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
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The following clinically significant immune-mediated adverse
reactions occurred at an incidence of <1% (unless otherwise
noted) in patients who received KEYTRUDA or were reported
with the use of other anti–PD-1/PD-L1 treatments. Severe or
fatal cases have been reported for some of these adverse
reactions. Cardiac/Vascular: Myocarditis,
pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and
Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ
transplant rejection.
Infusion-Related Reactions
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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)
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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
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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-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%).
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.
Before prescribing KEYTRUDA® (pembrolizumab), please read the accompanying Prescribing Information. The Medication Guide also is available.
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US-OGA-00601 12/23