2240P Novel genetic markers associated with immune checkpoint inhibitor induced immune-related adverse events

Immune checkpoint inhibitors (ICI) are highly efficacious but ∼ 50% of cancer patients on combination and ∼10% on ICI monotherapy experience ≥ grade 3 immune-related adverse events (irAE). Managing irAEs is challenging and there is a lack of predictive biomarkers. We conducted genome-wide association analyses (GWAS) to identify markers associated with irAEs. 599 cancer patients on ICIs were genotyped and genome-wide imputation was performed. Association testing with CTCAE graded irAEs was conducted (0=grade 0-2, 1=grade ≥3 irAE). Markers with P<5x10-6 were tested in a validation cohort. A transcriptome-wide association study (TWAS) was also performed. 72% of the discovery cohort had melanoma, 37% received combination therapy and 31% developed ≥ grade 3 irAE. 8 SNPs were associated with any ≥ grade 3 irAE at P<5x10-6 but none replicated at P<0.05 (Table 2240P). Of note one, rs35429660, is significantly associated with ZNF701 expression in monocytes and ZNF701 was also significant in the TWAS (P=5.1x10-7). In an analysis of individual organ irAEs, we identified markers at P<5x10-6 in the discovery phase. One, rs77941834, was associated with hepatitis in the validation phase (P=0.04) and expression of LINC02021 in T cells (4.6 x10-8). 11 other SNPs had suggestive evidence of validation. One maps to MAST3, linked to inflammatory bowel disease and another maps to IFI44, linked to multisystem inflammatory syndrome, viral hepatitis and immune cell infiltration. The IL7 SNP previously reported as associated with any grade irAE at GWAS significance was nominally significant (P=0.05) in our data. Table: 2240PMarkers associated with any ≥ grade 3 irAE at P<5x10-6 in discovery phasersIDToxicity associated alleleDiscovery OR (95% CI)Discovery P-valueValidation OR (95% CI)Validation P-valueMeta P-valuers1310844785TTG2.5(1.8-3.6)8.91 x 10-80.8(0.6-1.2)0.260.0038rs7197466T2.1(1.5-2.9)2.19 x 10-61(0.8-1.4)0.810.00077rs35429660C2.2(1.6-3)5.13 x 10-71.2(0.8-1.6)0.367.32 x 10-5rs1389216733CA6.3(2.6-15.7)3.07 x 10-61.6(0.8-3.5)0.180.0004rs6864863A2.1(1.5-2.9)3.73 x 10-60.8(0.6-1)0.070.11rs4527728T2.2(1.6-3.1)2.68 x 10-61.2(0.9-1.6)0.260.00012rs1208547611CTT2.5(1.7-3.7)3.59 x 10-61.1(0.7-1.5)0.790.0015rs2472135A2.1(1.6-2.8)5.83 x 10-71.1(0.8-1.5)0.437.98 x 10-5 Open table in a new tab We identified novel variants, including an immune eQTL for ZNF701, associated with serious ICI induced irAE. None reached genome-wide significance (P<5x10-8). Meta-analysis with other cohorts is required to confirm our results and identify further markers predictive of irAE risk.