What are the side effects of ipilimumab (Yervoy)?

Side Effects of Ipilimumab (Yervoy)

Ipilimumab causes immune-related adverse events (irAEs) in 60-85% of patients, with 10-27% developing severe grade 3-4 toxicities and approximately 2% experiencing potentially fatal reactions. 1

Common Side Effects

Ipilimumab as a single agent commonly causes the following adverse reactions (occurring in ≥20% of patients):

• Fatigue
• Diarrhea
• Pruritus (itching)
• Rash
• Nausea
• Headache 2

Immune-Related Adverse Events (irAEs)

Ipilimumab's mechanism of action involves immune system activation through CTLA-4 blockade, which can lead to immune-mediated inflammation of various organs:

Gastrointestinal

• Colitis/Diarrhea: Most common irAE, can be severe and potentially life-threatening 1
• Can lead to bowel perforation if severe and not promptly treated 3

Dermatologic

• Skin reactions: Often the first irAEs to develop, typically within first 8-12 weeks of treatment 1
• Include rash, pruritus, and vitiligo

Hepatic

• Hepatitis: Manifests as elevated liver enzymes
• May require high-dose corticosteroids or additional immunosuppressants like mycophenolate mofetil 3

Endocrine

• Hypophysitis (inflammation of the pituitary gland)
• Thyroiditis
• Adrenal insufficiency
• Often require hormone replacement therapy 1

Pulmonary

• Pneumonitis: Less common but potentially serious 4
• Associated with worse survival outcomes compared to other irAEs 4

Other Less Common but Serious irAEs

• Neurological disorders: Can be severe and life-threatening
• Myocarditis: Rare but potentially fatal 1
• Nephritis: Can lead to renal dysfunction 2

Timing of Side Effects

Most irAEs begin within the first 8-12 weeks of treatment initiation, with skin toxicities typically appearing first 1. However, some adverse events can occur at any time during treatment or even after discontinuation 2.

Severity and Dose Relationship

The severity of side effects is dose-dependent:

• At 3 mg/kg (standard metastatic disease dose): 10-27% develop grade 3-4 toxicities 1
• At 10 mg/kg (adjuvant setting): 41.6% grade 3-4 irAE rate and 1.1% fatal irAE rate 1
• No grade 3-4 AEs observed at 0.3 mg/kg 1

Management Considerations

1. Early recognition is critical for effective management of irAEs
2. Corticosteroids are the mainstay of treatment for most moderate to severe irAEs
   • Typically prednisolone 1 mg/kg for moderate cases 3
   • Severe cases may require high-dose parenteral pulsed methylprednisolone 3
3. Additional immunosuppression may be needed for steroid-refractory cases:
   • Infliximab for steroid-refractory colitis 3
   • Mycophenolate mofetil for steroid-refractory hepatitis 3
4. Approximately 35% of patients require systemic corticosteroid treatment, and about 10% need additional immunosuppression with anti-TNFα therapy 5

Important Caveats

• Patients with underlying autoimmune disorders may be especially susceptible to serious immune-related reactions 1
• Treatment with immunosuppressants for irAEs does not appear to negatively impact overall survival or time to treatment failure 5
• The FDA approval of ipilimumab included a Risk Evaluation and Mitigation Strategy (REMS) due to potential toxicity 1
• Vigilant monitoring is essential as irAEs can affect any organ system and may occur even after treatment discontinuation 2

Combination Therapy Considerations

When ipilimumab is combined with nivolumab or chemotherapy, additional common adverse reactions include:

• Musculoskeletal pain
• Pyrexia
• Cough
• Decreased appetite
• Vomiting
• Abdominal pain
• Dyspnea
• Upper respiratory tract infection
• Arthralgia
• Hypothyroidism
• Constipation
• Decreased weight
• Dizziness 2