Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis

Abstract

Backgrounds: Immune checkpoint inhibitors (ICIs) are considered cornerstones of oncology treatment with durable anti-tumor efficacy, but the increasing use of ICIs is associated with the risk of developing immune-related adverse events (irAEs). Although ICI-associated pancreatic adverse events (AEs) have been reported in patients treated with ICIs, the clinical features and spectrum of pancreatic AEs are still not well-defined. Therefore, this study aimed to identify the association between pancreatic AEs and ICIs treatments and to characterize the main features of ICI-related pancreatic injury (ICIPI) based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: Data from the first quarter of 2015 to the first quarter of 2021 in the database were extracted to conduct a disproportionality analysis. The selection of AEs related to the pancreas relied on previous studies and preferred terms from the Medical Dictionary for Regulatory Activities. Two main disproportionality analyses-the reporting odds ratio (ROR) and information component (IC)-were used to evaluate potential associations between ICIs and pancreatic AEs.

Results: In total, 2,364 cases of pancreatic AEs in response to ICIs were extracted from the FAERS database, of which, 647 were identified as ICI-associated pancreatitis and 1,293 were identified as ICI-associated diabetes mellitus. Generally, significant signals can be detected between pancreatic AEs and all ICIs treatments (ROR₀₂₅ = 3.30, IC₀₂₅ = 1.71). For monotherapy, the strongest signal associated with pancreatitis was reported for anti-PD-L1 (ROR₀₂₅ = 1.75, IC₀₂₅ = 0.76), whereas that with diabetes mellitus was reported for anti-PD-1 (ROR₀₂₅ = 6.39, IC₀₂₅ = 2.66). Compared with monotherapy, combination therapy showed stronger associations with both ICI-associated pancreatitis (ROR₀₂₅ = 2.35, IC₀₂₅ = 1.20 vs. ROR₀₂₅ = 1.52, IC₀₂₅ = 0.59) and ICI-associated diabetes mellitus (ROR₀₂₅ = 9.53, IC₀₂₅ = 3.23 vs. ROR₀₂₅ = 5.63, IC₀₂₅ = 2.48), but lower fatality proportion.

Conclusions: ICIs were significantly associated with the over-reporting frequency of pancreatic AEs, in which combination therapy posed a higher reporting frequency. Therefore, patients should be informed of these potential toxicities before ICIs medications are administered.

Keywords: CTLA-4; FAERS; PD-1/PD-L1; combination therapy; diabetes mellitus; immune checkpoint inhibitors; pancreatic adverse events; pancreatitis.