Mutations Associated With High-Grade irAEs in NSCLC Patients Receiving Immunotherapies

•High-grade irAEs occur in around 15% of total immunotherapy treated NSCLC patients.•Respiratory related irAEs are the most popular among patients who developed high-grade irAEs.•Specific gene mutations were associated with the occurrence of high-grade irAEs.•Different subtypes of NSCLC have unique mutation signatures that were associated with high-grade irAEs. Compared to low-grade irAEs, high-grade irAEs are more often dose-limiting and can alter the long-term treatment options for a patient. Predicting the incidence of high-grade irAEs would help with treatment selection and therapeutic drug monitoring. We performed a retrospective study of 430 stage III and IV patients with non-small cell lung cancer (NSCLC) who received an immune checkpoint inhibitor (ICI), either with or without chemotherapy, at a single comprehensive cancer center from 2015 to 2022. The study team retrieved sequencing data and complete clinical information, including detailed irAEs medical records. Fisher's exact test was used to determine the association between mutations and the presence or absence of high-grade irAEs. Patients were analyzed separately based on tumor subtypes and sequencing platforms. High-grade and low-grade irAEs occurred in 15.2% and 46.2% of patients, respectively. Respiratory and gastrointestinal irAEs were the 2 most common irAEs. The distribution of patients with or without irAEs was similar between ICI and ICI+chemotherapy-treated patients. By analyzing the mutation data, we identified 5 genes (MYC, TEK, FANCA, FAM123B, and MET) with mutations that were correlated with an increased risk of high-grade irAEs. For the adenocarcinoma subtype, mutations in TEK, MYC, FGF19, RET, and MET were associated with high-grade irAEs; while for the squamous subtype, ERBB2 mutations were associated with high-grade irAEs. This study is the first to demonstrate that specific tumor mutations correlate with the incidence of high-grade irAEs in patients with NSCLC treated with an ICI, providing molecular guidance for treatment selection and drug monitoring. High grade immune-related adverse events (irAEs) in vital organs are likely to cause permanent discontinuation of ICI therapy, greatly affecting the efficacy of ICI as well as patients’ health conditions. This study analyzed the correlation between high-grade irAEs and tumor sequencing data from 430 nonsmall cell lung cancer (NSCLC) patients from 2015 to 2022. Our data suggest that specific gene mutations are associated with