Can the combination of ipilimumab (Ipilimumab) and nivolumab (Nivolumab) cause diarrhea?

Ipilimumab and Nivolumab Combination Therapy and Diarrhea

Yes, the combination of ipilimumab and nivolumab can definitely cause diarrhea, and it is one of the most common and potentially serious gastrointestinal immune-related adverse events (irAEs) associated with this therapy. 1

Incidence and Severity

The combination of ipilimumab and nivolumab significantly increases the risk of gastrointestinal adverse events compared to either agent alone:

• Combination therapy: 13.6% all-grade colitis, 9.4% severe colitis, and 9.2% severe diarrhea 1
• Ipilimumab monotherapy: 9.1% all-grade colitis, 6.8% severe colitis, and 7.9% severe diarrhea 1
• PD-1/PD-L1 inhibitors (like nivolumab) monotherapy: Only 1.3% all-grade colitis, 0.9% severe colitis, and 1.2% severe diarrhea 1

A 2019 study specifically found that patients receiving combination therapy were significantly more likely to experience gastrointestinal events compared to ipilimumab monotherapy patients (melanoma hazard ratio: 1.54; lung cancer hazard ratio: 2.93) 2.

Clinical Presentation

Diarrhea associated with ipilimumab/nivolumab typically presents as:

• Onset after approximately three infusions, though it can occur as early as after the first infusion 1
• May present with abdominal pain, rectal bleeding, mucus in stool, and fever 1
• Can range from mild, self-limited diarrhea to severe, life-threatening colitis 1
• May recur months after discontinuation of immunotherapy 1

Management Algorithm

1. Grade 1 (mild diarrhea, <4 stools/day over baseline):

   • Consider holding treatment, especially for combination therapy 1
   • Symptomatic management
   • Rule out infectious causes

2. Grade 2 (moderate diarrhea, 4-6 stools/day over baseline):

   • Hold ipilimumab/nivolumab combination therapy 1
   • Consider oral corticosteroids
   • If symptoms worsen or don't improve within 3-5 days, escalate to IV steroids

3. Grade 3-4 (severe diarrhea, ≥7 stools/day over baseline, life-threatening):

   • Permanently discontinue treatment 3
   • High-dose IV corticosteroids 1
   • If no improvement within 3-5 days of steroid therapy, consider infliximab 1
   • Hospitalization for severe cases

Important Considerations

• Diagnostic workup: Exclude infectious etiologies (stool culture, C. difficile, CMV PCR) before attributing diarrhea to immunotherapy 1
• Colonoscopy: May be necessary in severe or steroid-refractory cases, though endoscopic findings may not always correlate with symptom severity 1
• Steroid-refractory cases: Early administration of infliximab should be considered for severe cases not responding to steroids 4
• Monitoring: Close monitoring of electrolytes, renal function, and hydration status is essential in severe cases 4

Pitfalls to Avoid

1. Delayed recognition: Prompt recognition and management are crucial to prevent progression to severe colitis 4
2. Inadequate infectious workup: Always rule out infectious causes before attributing diarrhea to immunotherapy 1
3. Prolonged steroid use: Long-duration steroid treatment (>30 days) without infliximab has been associated with increased infection risk compared to shorter steroid courses plus infliximab 1
4. Failure to recognize severe cases: Severe colitis can lead to complications like bowel perforation and toxic megacolon if not managed aggressively 5
5. Resuming therapy too soon: For patients who have experienced significant gastrointestinal toxicity, careful consideration should be given before resuming therapy 1

Healthcare providers should be vigilant about these potential gastrointestinal complications when administering ipilimumab and nivolumab combination therapy and educate patients about promptly reporting symptoms to help prevent development of grade 3 adverse events 1.