Multi-ethnic genome-wide association study to identify a novel locus for susceptibility to immune-related adverse events from immune checkpoint inhibitors.

Abstract

3090 Background: Immune-related adverse events (IrAEs) arising from immune checkpoint inhibitors (ICIs) can be unpredictable. As genomic variation underlies both disease susceptibility and drug responses, genomic markers may predict for the development of IrAEs. We perform a pioneering pharmacogenomic study across a multi-ethnic Asian patient population to uncover genomic biomarkers associated with IrAEs from ICIs. Methods: From March 2018 – July 2023, cancer patients treated with ICIs from the National University Cancer Institute Singapore and Tan Tock Seng Hospital were recruited. IrAEs were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. DNA was extracted and genotyped by Infinium Global Screening Array (700K markers). Statistical analyses were performed by SVS/HelixTree, PLINK and R. Genetic association was performed by logistic regression (additive model), accounting for all possible confounding factors. Bonferroni corrected P < 1.28E-07 (0.05/390,925 SNPs passed QC) was considered statistically significant. Results: Genome-wide association study (GWAS) was conducted amongst 507 patients of Asian Ancestry (Chinese, Malay, Indian and Others). Median age was 63. Majority were male (66.5%), Chinese (76.7%), ECOG PS 0-1 (40.1%) and had stage IV cancer at diagnosis (67.2%). Non-small cell lung cancer (37.1%), renal cell carcinoma (12.2%) and hepatocellular carcinoma (7.7%) were the three most common cancers. Top four ICIs used were pembrolizumab, nivolumab, durvalumab and atezolizumab, respectively (47.1%, 23.9%, 12.5%, 11.3%). 0.8% of patients received dual ICIs concurrently. Median duration of treatment was 142 days and median follow-up was 147 days. IrAEs were seen in 43.7% of patients. Skin (24.1%), endocrine (8.1%) and hepatotoxicity (6.1%) were the most common IrAEs. 4.9% of patients had grade ≥3 toxicity, of which skin (3.6%), hepatotoxicity (3.0%) and pulmonary toxicity (1.8%) were the most common. Multi-ethnic GWAS analysis identified one potential novel genetic locus associated with CTCAE grade ≥3 IrAEs. chr3:163402331 rs146525069; P = 7.29E-08, OR (95%CI) = 17.08 (5.40- 54.04); minor allele = A, 10.91% in Cases vs 0.71% in Controls. Conclusions: This pharmacogenomics GWAS uncovered a novel locus for susceptibility to serious immune-related adverse events from immune checkpoint inhibitors. Further pharmacogenomic discovery/replication and functional validation studies are currently on-ongoing. Our study provides a potential biological mechanism for IrAEs and a step towards more effective clinical translation of pharmacogenetic testing to personalize ICI use.