What are the guidelines for using proton pump inhibitors (PPI) in adult cancer patients with a history of gastrointestinal issues, such as gastroesophageal reflux disease (GERD) or peptic ulcer disease, who are receiving pembrolizumab, a monoclonal antibody?

PPI Use with Pembrolizumab in Cancer Patients

Proton pump inhibitors should be avoided or discontinued when possible in cancer patients receiving pembrolizumab, as concomitant PPI use is associated with significantly worse survival outcomes, though patients with definitive indications (Barrett's esophagus, severe erosive esophagitis, or history of esophageal ulcer) should continue therapy with careful monitoring for immune-related gastritis. 1, 2

Evidence for PPI-Pembrolizumab Interaction

Survival Impact

• Concomitant PPI use in metastatic urothelial cancer patients receiving pembrolizumab was associated with significantly inferior progression-free survival (4.5 vs. 7.2 months, p=0.002) and overall survival (8.7 vs. 14.1 months, p<0.001) compared to non-users in a large real-world study of 802 patients. 1
• PPI use remained a significant independent predictor of worse PFS and OS after multivariate analysis, suggesting this is not simply confounding by indication. 1
• However, a smaller Japanese cohort study (n=79) did not reproduce these findings, showing no significant OS or PFS differences, highlighting some uncertainty in the evidence. 3

Proposed Mechanism

• PPIs significantly impair gut microbiome diversity, which is known to influence tumor response to immune checkpoint inhibitors. 3
• The mechanism of PPI interference with pembrolizumab efficacy warrants further elucidation but likely involves microbiome-mediated effects on immune response. 1

Risk of Immune-Related Gastritis

Clinical Presentation

• Pembrolizumab can cause immune-mediated acute gastritis presenting as symptomatic gastroesophageal reflux disease, which paradoxically may prompt PPI initiation. 4, 5
• Severe lymphoplasmacytic and neutrophilic infiltration on gastric biopsy characterizes pembrolizumab-related gastritis. 4
• Gastric ulcers may develop as part of this immune-related adverse event. 5

Critical Pitfall

• PPIs alone are insufficient to treat pembrolizumab-induced gastritis and gastric ulcers—these immune-related adverse events require systemic corticosteroids and potentially biologics like infliximab in severe cases. 5
• PPI therapy may mask early gastrointestinal symptoms of immune-related adverse events, particularly immune-mediated colitis, delaying recognition and treatment. 6
• Delayed recognition of immune-mediated colitis has resulted in fatal outcomes. 6

Management Algorithm

Step 1: Pre-Treatment Assessment

• Review all current medications and identify patients on PPIs before initiating pembrolizumab. 2
• Determine if the patient has a definitive indication for PPI therapy: Barrett's esophagus, severe erosive esophagitis (LA grade C/D), history of esophageal ulcer, or Zollinger-Ellison syndrome. 2

Step 2: PPI De-Prescribing Strategy

• For patients without definitive indications, discontinue PPI at least 30-60 days before pembrolizumab initiation. 1, 2
• For patients with nonerosive GERD (most GERD patients), attempt step-down to on-demand dosing or H2-receptor antagonists as alternatives. 2
• If twice-daily PPI is being used, step down to once-daily dosing to reduce complication risk. 2

Step 3: Patients Requiring Continued PPI

• For patients with definitive indications who must continue PPI, use the lowest effective dose and implement enhanced monitoring for immune-related gastrointestinal adverse events. 2, 6
• Assess for new-onset diarrhea, abdominal pain, blood in stool, or mucus in stool at each pembrolizumab infusion visit. 6
• Maintain a lower threshold for intervention given the masking effect of PPIs on early symptoms. 6

Step 4: Managing New GI Symptoms on Pembrolizumab

• If gastroesophageal reflux symptoms develop during pembrolizumab treatment, perform esophagogastroduodenoscopy with biopsy before initiating PPI therapy to rule out immune-mediated gastritis. 4, 5
• Diarrhea, nausea, decreased appetite, and constipation are common adverse events with pembrolizumab and should not automatically prompt PPI initiation. 6
• Immune-mediated colitis typically develops within the first 2 cycles but can occur at any time during treatment. 6

Step 5: Treatment of Confirmed Immune-Related Gastritis

• Initiate systemic corticosteroids as first-line therapy for pembrolizumab-induced gastritis or gastric ulcers—do not rely on PPI monotherapy. 5
• Consider extended steroid therapy as gastritis and ulcers may improve slowly over months. 5
• Reserve infliximab or other biologics for severe, steroid-refractory cases. 5

Special Considerations with Combination Therapy

• When pembrolizumab is combined with chemotherapy, diarrhea incidence and grade ≥3 diarrhea risk increase, necessitating more frequent GI symptom assessment. 6
• Elevated liver enzymes, nausea, and vomiting are more frequent with combination regimens. 6
• A lower threshold for intervention is warranted given higher baseline toxicity rates with combination therapy. 6

Additional PPI Safety Concerns in Cancer Patients

• Long-term PPI use carries specific risks particularly relevant to cancer patients: bone fractures, Clostridium difficile infection, hypomagnesemia, acute interstitial nephritis, community-acquired pneumonia, and nutritional deficiencies. 2, 7
• Higher-dose PPIs show stronger associations with these complications. 2
• Cancer patients may be at increased risk for C. difficile and other enteric infections due to PPI-induced acid suppression. 7