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.

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

• The most common adverse reactions for
  KEYTRUDA (reported in ≥20% of patients)
  were fatigue, musculoskeletal pain, rash,
  diarrhea, pyrexia, cough, decreased appetite,
  pruritus, dyspnea, constipation, pain,
  abdominal pain, nausea, and hypothyroidism.

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.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®) for Colon Cancer V.1.2023.
© National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 31, 2023. To view the most recent and complete version of the guidelines, go online to NCCN.org. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.1.2023.
© National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed March 31, 2023. To view the most recent and complete version of the guidelines, go online to NCCN.org. 3. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology.
J Clin Oncol. 2017;35(13):1453-1486. doi:10.1200/JCO.2016.71.9807 4. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Am J Gastroenterol. 2014;109:1159-1179. 5. Rubenstein JH, Enns R, Heidelbaugh J, et al. American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology. 2015;149:777-782.

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