Novel Blood-Based Biomarker Predicting Severe Toxicity In Melanoma Anti-Ctla-4 Immunotherapy Treatment.

3077 Background: Immune checkpoint inhibition (ICI) has improved clinical outcomes of metastatic melanoma (MM). However, 65-80% of treated patients experience immune-related adverse events (irAEs), urging for the availability of personalized and easy-access clinical biomarkers. We have previously shown that germline genetics related to host immunity affects ICI response and MM survival. In this study, we investigated if germline immune-related expression quantitative trait loci (ieQTLs) may predict ICI-induced irAEs in MM. Methods: Through a comprehensive interrogation of a healthy twin-cohort expression dataset (MuTHER), we identified 40 ieQTLs most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped using the MassARRAY system in anti-CTLA-4-treated MM patients, collected as part of a multi-institutional collaboration. Using multivariable logistic regression models, we tested the association of 40 ieQTLs with irAEs in a discovery cohort of 97 MM patients followed by a validation in additional cohort of 97 anti-CTLA-4 treated patients. Results: We found rs7036417 significantly associated with severe anti-CTLA-4 irAEs in the discovery (OR = 6.18; 95%CI = 1.61-23.74; p = 0.007) and validation (OR = 6.73, 95%CI = 1.42-31.86; p = 0.02) cohorts. Pooled analysis showed that carriers of two rs7036417 alternate alleles (TT) have a 6-fold increased risk of developing severe irAEs (OR = 6.11; 95% = 2.26-16.56;p = 0.0003). This association was not observed with ICI response or survival. The alternate allele of rs7036417 is associated with higher expression of SYK (spleen-associated tyrosine kinase), suggesting that elevated SYK contributes to developing severe irAEs. Conclusions: We report that rs7036417, an ieQTL in SYK, associates with an increased risk of severe irAEs, independent of ICI efficacy. SYK plays an important role in B-cell/T-cell expansion and increased pSYK has been reported in patients with rheumatoid arthritis or systemic lupus erythematosus. Based on our data, the over-expression of SYK likely explains the biological mechanisms of the association between rs7036417 and anti-CTLA4 irAEs. These findings propose a novel blood-based baseline biomarker stratifying the patients at increased risk of severe irAEs, with a clinical effect substantially surpassing those observed for currently available predictors. Our ongoing studies are currently investigating SYK eQTL as a novel target in toxicity-reducing therapies.