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.

Pancreatic injury following immune checkpoint inhibitors: A systematic review and meta-analysis

“…In 35,223 patients from 50 RCTs, the all-grades PI incidence was 2.22% (95% CI = 1.94–2.53%), which was less than previous similar studies ( George et al, 2019 ; Su et al, 2018 ; Zhou et al, 2021 ). This study aligns with previous studies ( George et al, 2019 ; Su et al, 2018 ; Zhang et al, 2022 ; Petrelli et al, 2021 ) and confirms that the incidence of PI with combined ICI use is significantly higher than that of single ICI. Furthermore, a previous study exploring the safety of more than 2 ICIs suggested that the incidence of elevated lipase was as high as 7.2% (95% CI = 5.2–9.9) ( Zhou et al, 2021 ), which is significantly higher than these results.…”

Drug‐Induced Acute Pancreatitis: A Real‐World Pharmacovigilance Study Using the FDA Adverse Event Reporting System Database

“…To some extent, such difference is largely attributed to the fact that immune‐mediated pancreatitis is the unique toxic effect of ICIs on the pancreas, which lead to the aggregation of ICIs‐related AE reports in the PT of immune‐mediated pancreatitis ( Figure ) and the corresponding increase of signal strength. The toxic effect of ICIs is different from other drug classes in that it specifically enhances immune responses by promoting T lymphocyte activity systematically, thereby facilitating a range of autoimmune toxicity potentially against pancreas and resulting in irreversible lesions (e.g., type 1 diabetes mellitus caused by autoimmune attack on pancreatic cells) and other potentially life‐threatening conditions 41 . Due to the wide application of ICIs at present and the great harm of pancreatic AEs, it is necessary to comprehensively understand the detailed safety profile of ICIs induced AP for further prevention and management.…”

“…Although some antineoplastic agents, such as immune checkpoint inhibitors (ICIs), L-asparaginase (or pegaspargase), and vascular endothelial growth factor receptor tyrosine kinase inhibitors, are known to significantly increase the risk of AP, [37][38][39] the quantity proportion of antineoplastic agents are not obviously predominant in the list of drugs summarized based on ADR reporting systems or literature review. [16][17][18][20][21][22][23][24][25]36 In our opinion, this discrepancy may be mainly attributed to the development and clinical application of novel antitumor drugs in recent years and the gradually recognized AP risk of it, 37,[39][40][41] whereas our research opportunely caught a glimpse of the emerging risk role of antineoplastic agents in inducing AP due to incorporating the real-time AP risk information of drugs. Furthermore, in order to further summarize the distribution characteristics of AP culprit-drugs, we made statistics on the top 10 drugs and drug classes with the highest reporting quantity proportion at the SMQ level and PT level (Figures 3, 4), respectively.…”

“…To cope with this problem, we introduced disproportionality analysis as a substitute to quantify the AP risk of each drug. In the previous study, this method was used to evaluate the risk of pancreatitis induced by ICIs, 41 glucocorticoids, 44 sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, 45 protease inhibitors, 46 and some single drugs (e.g., tocilizumab, eluxadoline, and blinatumomab). [47][48][49] To a certain degree, these studies revealed the risk of AP caused by some drugs, which can provide guiding information for the clinic.…”

Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system

“…In the present study, the disproportionality analysis was used to analyze the safety data of semaglutide to quantitative gastrointestinal positive signals based on FAERS database, which was a global, public and accessable pharmacovigilance database ( 14 , 15 ). Further, stratification analysis, clinical priority of signals, time-to-onset, and the serious outcomes were performed to detect the characteristics of semaglutide-associated gastrointestinal AEs.…”