Side Effects of Pembrolizumab
Pembrolizumab causes immune-related adverse events (irAEs) in 73-80% of patients, with grade 3 or higher toxicity occurring in 10-16% of cases, primarily affecting the skin, gastrointestinal tract, endocrine system, liver, and lungs. 1
Common Side Effects by Organ System
Dermatologic (Most Common)
- Rash and pruritus occur in 30-40% of patients 2
- Maculopapular rash is the most frequent presentation
- Vitiligo develops in approximately 8% of melanoma patients (associated with better tumor response)
- Onset typically within days to weeks, though can be delayed months
- Rare but life-threatening: Stevens-Johnson Syndrome/TEN and DRESS syndrome require immediate discontinuation 2
Gastrointestinal
- Diarrhea and colitis are prominent
- Nausea (26% in combination with chemotherapy) 3
- Vomiting (26-29% in pediatric patients) 3
- Rare postmarketing: exocrine pancreatic insufficiency and sclerosing cholangitis 3
Endocrine Disorders
- Thyroid dysfunction is particularly common:
- Median onset: 28.6 weeks for endocrine toxicities 1
- Risk significantly increased when combined with lenvatinib (p=0.041) 5
Hepatotoxicity
- Increased ALT (60% all grades, 11% grade 3-4) 3
- Increased AST (57% all grades, 9% grade 3-4) 3
- Increased hepatic enzymes (ROR = 2.25) 4
- Median onset: 7.4 weeks 1
Pulmonary
Hematologic Abnormalities
- Anemia (90% all grades, 20% grade 3-4) 3
- Neutropenia (78% all grades, 50% grade 3-4) 3
- Lymphopenia (73% all grades, 28% grade 3-4) 3
- Thrombocytopenia (54% all grades, 19% grade 3-4) 3
Rare but Severe Immune-Related Adverse Events
Cardiac
- Myocarditis is rare but potentially fatal 6
- Higher risk when bulbar or ocular muscle involvement present 7
- Requires immediate recognition and aggressive immunosuppression
Neurologic
- Myasthenia gravis (can worsen pre-existing disease) 8
- Encephalitis and CNS demyelination 6, 8
- Myositis/myopathy:
- Demyelinating polyneuropathy 8
Metabolic
- Diabetic ketoacidosis can occur acutely 6
- Type 1 diabetes mellitus development
Renal
- Nephritis with median onset: 50.9 weeks 1
Critical Timing Considerations
Most adverse events occur within 0-30 days of administration 4, though:
- Endocrine toxicities: median 28.6 weeks
- Renal toxicities: median 50.9 weeks
- Gastrointestinal: median 26.3 weeks 1
Special Populations
Pediatric Patients
Pediatric patients experience higher rates of:
- Pyrexia (33% vs. lower in adults) 3
- Vomiting (29% vs. lower in adults) 3
- Headache (25% vs. lower in adults) 3
- Abdominal pain (23% vs. lower in adults) 3
- Leukopenia (30% higher rate) 3
- Neutropenia (28% higher rate) 3
- Thrombocytopenia (22% higher rate) 3
Geriatric Patients
Patients ≥65 years have a 50% incidence of serious adverse reactions vs. 24% in younger patients 3
Pregnancy and Reproductive Considerations
Pembrolizumab can cause fetal harm through:
- Disruption of maternal-fetal immune tolerance
- Increased risk of abortion or stillbirth 3
- Potential for immune-mediated disorders in offspring
- Contraception required during treatment and for 4 months after last dose 3
- Breastfeeding contraindicated during treatment and for 4 months after 3
Prognostic Indicator
Paradoxically, patients who develop adverse reactions demonstrate better clinical outcomes than those without toxicity 5, suggesting immune activation correlates with therapeutic response.
Management Principles
Corticosteroids are the cornerstone of irAE management 2: