What are the potential adverse reactions of Keytruda (pembrolizumab)?

Keytruda (Pembrolizumab) Adverse Reactions

Pembrolizumab (Keytruda) commonly causes fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain, but its most concerning adverse reactions are immune-mediated effects including colitis, hepatitis, endocrinopathies, pneumonitis, and nephritis which can be severe or fatal. 1

Common Adverse Reactions

General Symptoms

• Fatigue (most common, affecting up to 70% of patients) 1, 2
• Pyrexia/fever (28%) 2
• Decreased appetite (21-23%) 1, 2

Gastrointestinal Effects

• Nausea (44-67%) 1, 2
• Diarrhea (28-41%) 1, 2
• Constipation (28-42%) 2
• Vomiting (26-31%) 2
• Abdominal pain (24%) 2
• Stomatitis (34%) 2

Skin Reactions

• Rash (26-52%) 1, 2
• Pruritus (common) 1
• Alopecia (34-61%) 2

Neurological Effects

• Headache (20-30%) 1, 2
• Peripheral neuropathy (41%) 2

Respiratory Effects

• Cough (23-26%) 1, 2
• Dyspnea (reported) 1

Immune-Mediated Adverse Events (irAEs)

These are the most serious potential complications of pembrolizumab therapy:

Pulmonary irAEs

• Pneumonitis (inflammation of lung tissue) 1, 3
  • Can range from mild to life-threatening
  • Requires immediate evaluation when suspected
  • Grade 3-4 pneumonitis requires permanent discontinuation of pembrolizumab 3

Gastrointestinal irAEs

• Colitis (inflammation of the colon) 1, 3
  • Can present with diarrhea, abdominal pain, blood in stool
  • Grade 3-4 colitis requires permanent discontinuation of pembrolizumab 3
• Exocrine pancreatic insufficiency (post-marketing) 2

Hepatic irAEs

• Hepatitis (liver inflammation) 1, 3
  • Presents with elevated liver enzymes (AST, ALT), bilirubin
  • Grade 3-4 hepatitis requires permanent discontinuation 3
• Sclerosing cholangitis (post-marketing) 2

Endocrine irAEs

• Thyroid disorders (hypothyroidism, hyperthyroidism) 1, 3, 4
• Adrenal insufficiency including isolated ACTH deficiency 3, 5
• Type 1 diabetes with hyperglycemia 3

Renal irAEs

• Nephritis (kidney inflammation) 1, 3
• Acute renal failure 4

Neurological irAEs

• Severe neurological toxicity 4

Hematologic irAEs

• Severe neutropenia (rare but reported) 6

Other irAEs

• Myositis/polymyositis (muscle inflammation) 4
• IgE-mediated anaphylaxis (rare) 7

Laboratory Abnormalities

Common laboratory abnormalities include:

• Anemia (90-97%) 2
• Leukopenia (85-93%) 2
• Neutropenia (78-88%) 2
• Lymphopenia (73-79%) 2
• Thrombocytopenia (54-57%) 2
• Elevated liver enzymes (ALT 60-70%, AST 57-65%) 2
• Hyperglycemia (52-63%) 2
• Hypoalbuminemia (34-36%) 2

Timing of Adverse Events

• Most irAEs develop within weeks to 3 months after starting treatment 3
• Some irAEs can occur as late as 1 year after discontinuation 3
• Monitoring should continue for at least 12 months after the last dose 3

Management of Adverse Events

Grading and Response Algorithm

1. Grade 1 (Mild): Continue pembrolizumab with close monitoring 3
2. Grade 2 (Moderate): Withhold pembrolizumab, initiate corticosteroids 3
3. Grade 3-4 (Severe): Permanently discontinue pembrolizumab, initiate high-dose corticosteroids 3
4. Steroid-refractory cases: Consider additional immunosuppressants (infliximab, mycophenolate mofetil) 3

Specific Management Approaches

• Pneumonitis: Withhold for Grade 2, permanently discontinue for Grade 3-4 3
• Colitis: Permanently discontinue for Grade 3-4 3
• Endocrinopathies: May continue pembrolizumab with appropriate hormone replacement 3
• Hepatitis: Withhold for moderate cases, permanently discontinue for severe cases 3
• Nephritis: Withhold for moderate cases, permanently discontinue for severe cases 3

Monitoring Recommendations

• Baseline and regular monitoring of complete blood count, comprehensive metabolic panel, thyroid function tests, morning cortisol, and ACTH 3
• Monitor for symptoms of irAEs at each visit and between visits 3
• Patients should immediately report new or worsening symptoms such as cough, shortness of breath, diarrhea, abdominal pain, or skin rashes 3

Clinical Pearls and Pitfalls

• irAEs can affect multiple organ systems simultaneously (e.g., concurrent renal failure, neurological toxicity, and hyperthyroidism) 4
• Pre-existing autoimmune conditions may increase risk of severe irAEs 6
• Some irAEs may require lifelong hormone replacement therapy even after discontinuation of pembrolizumab 3
• Fatal adverse reactions have been reported in 2.5% of patients receiving pembrolizumab in combination with chemotherapy 2
• Early recognition and prompt management of irAEs is critical to prevent progression to severe or life-threatening complications 3