Can Keytruda cause severe diarrhea?

October 15, 2025 •

4 min read

Over 20% of patients receiving Keytruda (pembrolizumab) in clinical trials have reported experiencing diarrhea. While often mild, this gastrointestinal side effect can sometimes escalate to severe immune-mediated colitis, which is inflammation of the colon caused by the medication's effect on the immune system.

Quick Summary

Keytruda can trigger immune-mediated colitis, presenting as diarrhea that can range from mild to severe and may require treatment interruption. The mechanism involves T-cell overactivation, potentially attacking healthy gut tissue. Management depends on severity, ranging from supportive care for mild cases to corticosteroids and immunosuppressants for more serious inflammation.

Key Points

Immune-mediated colitis is the cause: Keytruda-induced severe diarrhea is a result of immune-mediated colitis, an immune-related adverse event (irAE) where the hyperactivated immune system attacks the colon.
Severity can range widely: While a common side effect of Keytruda, diarrhea can be mild in most cases, but in a minority of patients, it can become severe and debilitating, requiring medical intervention.
Seek immediate medical attention for severe symptoms: Symptoms like severe abdominal pain, cramping, blood or mucus in the stool, and very frequent bowel movements warrant immediate contact with your healthcare provider.
Management is based on severity: Treatment varies from supportive care and medication pauses for mild cases to high-dose corticosteroids for moderate-to-severe colitis.
Steroid-refractory cases need further treatment: If corticosteroids are ineffective, alternative immunosuppressive medications like infliximab or vedolizumab may be necessary to resolve the inflammation.
Do not take anti-diarrheal agents in suspected colitis: If immune-mediated colitis is suspected, conventional anti-diarrheal agents should be avoided until an infectious cause is ruled out.
Collaboration with your care team is vital: Open communication with your oncologist about any changes in symptoms is the most important step for effective management.
Early detection improves outcomes: Recognizing and treating immunotherapy side effects as soon as they arise can help prevent them from becoming more serious and interfering with cancer treatment.

The Mechanism Behind Keytruda-Induced Diarrhea

Keytruda (pembrolizumab) is an immunotherapy medication, specifically a type of immune checkpoint inhibitor (ICI). Its purpose is to boost the body's immune response against cancer cells by blocking the PD-1 protein, which cancer cells use to hide from the immune system. While effective, this heightened immune activity can sometimes turn against healthy tissues and organs, a phenomenon known as an immune-related adverse event (irAE).

Diarrhea caused by Keytruda is often a manifestation of immune-mediated colitis, or inflammation of the colon. The precise mechanism is not fully understood, but it is thought to involve the overactivation of T-cells. The charged-up T-cells, which are meant to attack cancer, instead infiltrate and inflame the intestinal lining, leading to symptoms like diarrhea, abdominal pain, and in severe cases, bloody stools.

Incidence and Severity of Keytruda-Related Diarrhea

Clinical trials have shown that diarrhea is a relatively common side effect of Keytruda, with over 20% of patients reporting it. The severity, however, can vary significantly. In most cases, it is a mild, manageable inconvenience. In a smaller subset of patients, it can progress to more serious and potentially life-threatening colitis.

For pembrolizumab monotherapy, the incidence of high-grade (Grade 3 or 4) colitis—which is often associated with severe diarrhea—is relatively low, occurring in approximately 1.3% to 2.9% of patients. When Keytruda is used in combination with other treatments, such as chemotherapy or other immunotherapies, the risk of developing severe diarrhea and colitis can increase. For instance, a meta-analysis found that combination regimens including ICIs could result in a higher incidence of all-grade diarrhea (17%-56%), though severe colitis incidence remained low.

Diagnosing Immune-Mediated Colitis

Proper diagnosis is crucial to differentiate Keytruda-induced diarrhea from other potential causes, such as infections or other treatment-related toxicities. The diagnostic process typically involves:

Excluding infectious causes: Stool cultures and tests for pathogens like C. difficile, bacteria, and parasites are performed to rule out infection.
Endoscopic evaluation: A colonoscopy is often necessary for persistent or severe cases. This allows clinicians to visualize the inflammation and take biopsies for histopathological analysis, which confirms the diagnosis of immune-mediated colitis.
Monitoring biomarkers: Fecal calprotectin, a protein released during intestinal inflammation, can be used to monitor disease activity and help guide treatment decisions.

Management Strategies for Keytruda-Induced Diarrhea

The management approach for Keytruda-induced diarrhea is graded based on severity. It's essential to communicate any changes in bowel habits to your healthcare provider immediately.

Treatment for Mild to Moderate Diarrhea (Grade 1-2)

For mild cases, typically defined as an increase of up to four bowel movements per day, initial management may involve:

Holding immunotherapy: A temporary pause in Keytruda treatment may be required, depending on the severity.
Supportive care: Staying hydrated and following a bland diet (such as the BRAT diet: bananas, rice, applesauce, toast) is recommended.
Anti-diarrheal medication: Over-the-counter medications like loperamide can be used to manage symptoms, but should not be used in suspected immune colitis until infection is ruled out.

Treatment for Severe Diarrhea (Grade 3-4)

Severe diarrhea or confirmed immune-mediated colitis necessitates a more aggressive treatment plan. A permanent discontinuation of Keytruda is often required for Grade 4 symptoms.

Corticosteroids: High-dose corticosteroids, such as prednisone or methylprednisolone, are the standard first-line treatment. These drugs help suppress the immune system and reduce intestinal inflammation. Early intervention with steroids is key.
Hospitalization: Severe cases may require inpatient care to manage dehydration, electrolyte imbalances, and intensive steroid therapy.
Second-line immunosuppression: If symptoms do not improve with steroids within a few days, additional immunosuppressants may be necessary. Common options include the anti–tumor necrosis factor (TNF) agent infliximab or the integrin antagonist vedolizumab.

Comparison of Diarrhea Management by Severity


Feature	Mild Diarrhea (Grade 1)	Moderate Diarrhea (Grade 2)	Severe Diarrhea (Grade 3)	Life-Threatening Diarrhea (Grade 4)
Symptom Description	≤3 additional bowel movements per day; no abdominal pain or mild cramping.	4-6 additional bowel movements per day; moderate abdominal pain.	≥7 additional bowel movements per day; severe abdominal pain, signs of incontinence.	Life-threatening consequences; urgent intervention required.
Keytruda Status	Continue with close monitoring; may consider holding on a case-by-case basis.	Hold treatment immediately.	Hold treatment immediately.	Permanently discontinue treatment.
Primary Treatment	Symptomatic management with loperamide (after infection ruled out); dietary modification.	Oral or IV corticosteroids.	IV corticosteroids.	IV corticosteroids.
Secondary Treatment	None, unless worsens.	Infliximab or vedolizumab if no response to steroids.	Infliximab or vedolizumab if no response to steroids.	Infliximab, vedolizumab, or other aggressive immunosuppression if steroid-refractory.
Clinical Setting	Outpatient.	May require hospital admission for monitoring.	Hospital admission required.	Hospital admission and intensive care required.

Conclusion

Yes, Keytruda can cause severe diarrhea as an immune-related adverse effect, though the incidence of severe cases is significantly lower than for mild cases. The underlying mechanism involves the activation of the immune system leading to intestinal inflammation, known as colitis. Awareness of this risk and prompt communication with your healthcare team are critical for effective management. Treatment strategies are tailored to the severity of the symptoms, ranging from supportive care and holding the immunotherapy for milder episodes to high-dose corticosteroids and other immunosuppressants for more severe, life-threatening inflammation. Early detection and appropriate management can effectively resolve the condition and prevent further complications.

This article is for informational purposes only and does not constitute medical advice. Please consult with your oncologist or healthcare provider for personalized guidance regarding your cancer treatment.

Frequently Asked Questions

The incidence of severe (Grade 3 or 4) colitis, which causes severe diarrhea, is relatively low with Keytruda monotherapy, occurring in about 1.3%-2.9% of patients in clinical trials. The risk may increase when Keytruda is combined with other treatments.

Immunotherapy-induced diarrhea most commonly appears within the first six weeks of treatment, but it can occur at any point during or even after treatment has concluded.

Signs of severe diarrhea include frequent loose bowel movements (more than seven per day), severe abdominal cramping, blood or mucus in the stool, fever, and dehydration.

You should immediately contact your oncologist or healthcare provider to inform them of your symptoms. They will determine the severity and guide you on the next steps, which may include stopping Keytruda temporarily and starting other medications.

Yes. Unlike typical diarrhea, which might be managed with over-the-counter medications, severe Keytruda-induced diarrhea is caused by an immune response. It requires specific treatment, usually with corticosteroids to suppress inflammation, and sometimes other immunosuppressive agents.

Whether you continue Keytruda depends on the severity of the colitis. For mild cases, treatment may continue with close monitoring. For moderate or severe cases, Keytruda is typically paused, and for life-threatening cases, it is permanently discontinued.

For mild symptoms, a bland, low-fiber, and lactose-free diet is often recommended to reduce irritation to the digestive tract. Avoiding spicy, greasy, or acidic foods, as well as caffeine and alcohol, may also help.