What are the side effects of Keytruda (pembrolizumab)?

Side Effects of Keytruda (Pembrolizumab)

Keytruda (pembrolizumab) commonly causes fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain, but its most serious adverse effects are immune-mediated conditions including colitis, hepatitis, endocrinopathies, pneumonitis, and nephritis. 1

Common Side Effects

Keytruda's most frequently reported adverse events include:

• General symptoms:

  • Fatigue/asthenia (reported in up to 56% of patients)
  • Fever/pyrexia
  • Decreased appetite/anorexia

• Gastrointestinal:

  • Nausea (up to 56%)
  • Constipation (35%)
  • Diarrhea (31%)
  • Vomiting (24%)

• Dermatologic:

  • Rash (25%)
  • Pruritus (itching)

• Respiratory:

  • Cough (21%)
  • Dyspnea (shortness of breath) (21%)

• Musculoskeletal:

  • Musculoskeletal pain

Immune-Mediated Adverse Events

The most concerning side effects of Keytruda are immune-mediated adverse events that can affect multiple organ systems:

1. Gastrointestinal:

   • Colitis (inflammation of the colon)
   • Can range from mild diarrhea to severe, life-threatening colitis

2. Hepatic:

   • Hepatitis (liver inflammation)
   • Elevated liver enzymes (ALT/AST)

3. Endocrine:

   • Thyroid disorders (hypothyroidism or hyperthyroidism)
   • Hypophysitis (pituitary inflammation)
   • Adrenal insufficiency (can occur up to 8 months after stopping treatment) 2
   • Type 1 diabetes mellitus 3

4. Pulmonary:

   • Pneumonitis (lung inflammation)
   • Can be life-threatening if not detected early

5. Renal:

   • Nephritis (kidney inflammation)
   • Acute kidney injury 4

6. Neurological:

   • Peripheral neuropathy
   • Severe neurological toxicity (rare) 4

7. Hematologic:

   • Rare cases of thrombotic thrombocytopenic purpura 5

8. Other immune-related effects:

   • Hepatitis B reactivation in carriers 6
   • Polymyositis (muscle inflammation) 4

Timing of Side Effects

Immune-related adverse events typically occur early in treatment (within weeks to 3 months after starting Keytruda), but can appear at any time during treatment and even up to a year after discontinuation 1. This delayed onset is particularly important to monitor, as evidenced by cases of adrenal insufficiency occurring 8 months after stopping treatment 2.

Risk Factors and Monitoring

Patients with pre-existing autoimmune conditions are at higher risk for exacerbation of their condition while on Keytruda. Before starting treatment, patients should undergo:

• Complete medical history, including autoimmune conditions
• Baseline laboratory tests (liver function, thyroid function, etc.)
• Radiological examinations as appropriate

Management of Side Effects

The management of immune-related adverse events generally follows a stepwise approach:

1. Mild symptoms (Grade 1): Often can continue treatment with close monitoring
2. Moderate symptoms (Grade 2): May require temporary treatment interruption and corticosteroids
3. Severe symptoms (Grade 3-4): Require permanent discontinuation of Keytruda and high-dose corticosteroids

For specific severe immune-mediated reactions:

• Colitis: High-dose steroids; may require infliximab for steroid-refractory cases
• Pneumonitis: High-dose steroids; may require additional immunosuppression if not improving
• Hepatitis: High-dose steroids; monitor liver enzymes closely
• Endocrinopathies: Hormone replacement therapy (often permanent)
• Nephritis: High-dose steroids; renal replacement therapy if severe 4

Important Considerations

• Immune-related adverse events can occur in any organ system and may present with nonspecific symptoms
• Early recognition and prompt management are critical to prevent serious complications
• Some endocrinopathies may require lifelong hormone replacement therapy
• Patients should be educated about potential side effects and instructed to report new symptoms promptly
• The risk-benefit ratio must be carefully considered, especially in patients with pre-existing autoimmune conditions

Keytruda's side effect profile reflects its mechanism of action as an immune checkpoint inhibitor, with most serious adverse events stemming from excessive immune activation against normal tissues.