Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System.

Xiaoyin Bai,Yang Yang,Hong Yang,Guanqiao Li,Gechong Ruan,Kaini Shen,Hongnan Zhen,Luo Wang,Junyi Ji,Yi Li,Shiyu Jiang,Yangzhong Zhou

doi:10.3389/fphar.2021.720776

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, immune-related adverse events (irAEs) in the gastrointestinal (GI) system commonly occur. In this study, data were obtained from the US Food and Drug Administration adverse event reporting system between July 2014 and December 2020. Colitis, hepatobiliary disorders, and pancreatitis were identified as irAEs in our study. Reporting odds ratio (ROR) with information components (IC) was adopted for disproportionate analysis. A total of 70,330 adverse events were reported during the selected period, 4,075 records of which were associated with ICIs. GI toxicities have been reportedly increased with ICI, with ROR025 of 17.2, 6.7, and 2.3 for colitis, hepatobiliary disorders, and pancreatitis, respectively. The risks of colitis, hepatobiliary disorders, and pancreatitis were higher with anti-CTLA-4 treatment than that with anti-PD-1 (ROR025 2.6, 1.3, and 1.1, respectively) or anti-PD-L1 treatment (ROR025 4.8, 1.3, and 1.3, respectively). Logistic analysis indicated that hepatobiliary disorders and pancreatitis more frequently occurred in female patients (adjusted odds ratio, 1.16 and 1.52; both p < 0.05). Consistently, polytherapy was a strong risk factor for colitis (adjusted odds ratio 2.52, p < 0.001), hepatobiliary disorders (adjusted odds ratio 2.50, p < 0.001), and pancreatitis (adjusted odds ratio 2.29, p < 0.001) according to multivariate logistic analysis. This pharmacovigilance analysis demonstrated an increased risk of all three GI irAEs associated with ICI therapies. The comparative analysis offered supportive insights on selecting GI irAEs for patients treated with ICIs.

Highlights

The increasing clinical use of approved antibodies against programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has changed the paradigm of cancer treatment (Ackermann et al, 2020)
4,075 cases were reported with Immune checkpoint inhibitors (ICIs) treatment, including nivolumab (n 2,267), pembrolizumab (n 964), cemiplimab (n 8), atezolizumab (n 241), avelumab (n 22), durvalumab (n 76), and ipilimumab (n 1,615)
As an extensive pharmacovigilance analysis on GI immunerelated adverse events (irAEs) after ICI treatments obtained from the FAERS database, this study demonstrated that increased risk of colitis, hepatobiliary abnormalities, and pancreatitis was associated with ICI monotherapy or combination therapies

Summary

Introduction

The increasing clinical use of approved antibodies against programmed cell death protein 1 (PD-1) (pembrolizumab, nivolumab, and cemiplimab), programmed death-ligand 1 (PD-L1) (avelumab, atezolizumab, and durvalumab), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (ipilimumab) has changed the paradigm of cancer treatment (Ackermann et al, 2020). As the most common type, colitis more commonly occurs after the administration of anti-CTLA-4 antibodies (7–12%) than that of anti-PD-1/PD-L1 antibodies (3%) (Davies and Duffield, 2017). This proportion increased to 12–18% when combining CTLA-4 and PD-1/ PD-L1 inhibitors (Motzer et al, 2018). This study characterized the safety profiles of ICIs and performed a disproportionality analysis through data-mining using the US Food and Drug Administration adverse event reporting system (FAERS), a postmarketing safety surveillance database, aimed at providing the new insights into GI toxicities associated with different ICIs or their combination

Methods

Results

Conclusion