Zhang, Zhao

Background To determine whether antibiotic treatment is a risk factor for immune-related adverse events (irAEs) across different patients with cancer receiving anti-PD-1/PD-L1 therapies. Methods The retrospective analysis includes clinical information from 767 patients with cancer treated at Hunan Cancer Hospital from 2017 to 2020. The pharmacovigilance data analysis includes individual cases of 38,705 safety reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2014 to 2020, and 25,122 cases of safety reports from the World Health Organization database VigiBase from 2014 to 2019. All cases that received anti-PD-1/PD-L1 treatment were included. Multiomics data from patients across 25 cancer types were download from The Cancer Genome Atlas. Logistic regression and propensity score algorithm was employed to calculate OR of irAEs. Results Retrospective analysis of in-house patients showed that irAE potential risks are higher in all cancer (OR 2.12, 95% CI 1.38 to 3.22, false discovery rate (FDR) adjusted-p=1.93×10−3) and patients with lung cancer (OR 3.16, 95% CI 1.67 to 5.95, FDR adjusted-p=1.93×10−3) when using antibiotics. Potential risk of irAEs in patients with lung cancer with antibiotic treatment is significantly higher in FAERS (OR 1.39, 95% CI 1.21 to 1.59; FDR adjusted-p=1.62×10−5) and VigiBase (OR 1.32, 95% CI 1.09 to 1.59, FDR adjusted-p=0.05). Mechanistically, decreased microbial diversity caused by antibiotics use may increase the irAE risk through mediating the irAE-related factors. Conclusions Our study is the first to comprehensively demonstrate the associations of irAEs and antibiotic during anti-PD-1/PD-L1 therapy across a wide spectrum of cancers by analyzing multisource data. Administration of antibiotics should be carefully evaluated in patients with cancer treated by anti-PD-1/PD-L1 to avoid potentially increasing irAE risk.

Abstract Background Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy. Methods We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas omics data. We further validated our observations in 2 independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors. Results A meta-analysis using 13 clinical studies that reported on 1096 female patients (36.8%, 95% confidence interval [CI] = 35.0% to 38.5%) and 1886 male patients (63.2%, 95% CI = 61.5% to 65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19, 95% CI = 0.91 to 1.54, 2-sided P = .21). Multivariable logistic regression analysis of 12 225 patients from the Food and drug administration Adverse Event Reporting System (FAERS) and 10 979 patients from VigiBase showed no statistically significant difference in irAEs by sex. A propensity score algorithm used on multi-omics data for 6019 patients from The Cancer Genome Atlas found no statistically significant difference by sex for irAE-related factors or pathways. The retrospective analysis of 2 in-house patient cohorts validated these results (OR = 1.55, 95% CI = 0.98 to 2.47, false discovery rate = 0.13, for cohort 1; OR = 1.16, 95% CI = 0.86 to 1.57, false discovery rate = 0.39, for cohort 2). Conclusions We observed minimal sex-associated differences in irAEs among cancer patients who received immune checkpoint inhibitor therapy. It may be unnecessary to consider sex effects for irAE management in clinical practice.