Background: Immune checkpoint inhibitors (ICIs) are used to treat several malignancies but predispose to systemic autoimmune inflammation referred to as immune-related adverse events (irAE). Upper and lower gastrointestinal (GI) tract inflammation are commonly encountered toxicities. Proton pump inhibitors (PPIs) are frequently employed for management of immune-mediated upper GI toxicity. Previous studies have also suggested that these agents may worsen lower GI toxicity. Our study aims to observe the effect of PPI exposure on the incidence and severity of GI irAEs.
Method: This was a single-center retrospective chart review including all patients who received ICIs between 01/2010 and 12/2022. Patients were categorized based on prior PPI usage and screened for the development of an upper or lower GI toxicities. PPI use was counted if the medication was received at least three months before starting ICI and one year after the last ICI dose. Patient demographic information was also collected.
Results: 16,849 patients met study inclusion. Criteria. The majority were white (80.8%), male (59.1%), with a median age of 64 years (IQR: 55-72). Patients received ICI for a median of 84 days (IQR: 27-266) and were followed up for around 1 year (IQR: 0.4-2.3). Overall mortality due to any cause was 81% at the end of the study period. 2,046 (12.1%) patients received PPIs during exposure to ICI while the remaining 14,803 (87.9%) patients did not. The overall incidence of upper and lower GI toxicity was 2.3% and 4.1% respectively. Incidence of upper GI toxicity was higher (2.5%) among patients who received PD-1/L1 inhibition (vs. anti-CTLA4 or combination; p<0.001) while that of lower GI toxicity (5.2%) was higher among those who received combination immunotherapy (vs. monotherapy; p<0.001). 106 (5.2%) patients receiving PPI developed an upper GI toxicity compared to 281 (1.9%) who did not receive PPI (p<0.001). 139 (6.8%) patients receiving PPI developed a lower GI toxicity compared to 552 (3.7%) who did not receive PPI (p<0.001). Pantoprazole was the most used PPI (used for 2,032 patients).
Conclusions: Our study with the largest sample on the subject to date explores the impact of PPI use around the time of immunotherapy on the incidence of immune-mediated GI toxicity. Our preliminary findings show that PPI use during immunotherapy may increase the risk of developing a GI irAE in this population, supporting findings from previous studies. For the future, we aim to collect clinical information to compare the irAE severity between both groups to see whether PPI use may predispose to a more severe disease course.

Figure 1. Patient selection flowchart

Kei Takigawa

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