Abstract 5802: Somatic variant predictors of cutaneous immune-related adverse events in cancer patients treated with immunotherapy

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Cutaneous immune-related adverse events (cirAEs) affect nearly one-third of patients treated with immune checkpoint inhibitors (ICIs). Identifying patients at high risk for cirAE can help guide monitoring and therapeutic management. Whether tumor somatic mutations are associated with the risk of cirAE development remains unknown. We analyzed tumor somatic single nucleotide variants (SNVs) from a discovery cohort of 733 patients with stage III/IV melanoma receiving ICIs at Dana Farber Cancer Institute and Massachusetts General Hospital. CirAE development was determined by chart review. SNVs were detected by OncoPanel v1-3. Nonsynonymous SNVs were used to calculate tumor mutational burden (TMB) and determine gene mutation status. Logistic regression models were used to test the association between gene mutation status and the binary outcome cirAE, while Cox regression models were used to examine the association between TMB or gene mutation status with time to cirAE development. Models were adjusted for demographic covariates (age at ICI, sex, self-reported race/ethnicity) and clinical covariates (melanoma subtype and ICI type). To validate significant associations identified in the discovery cohort, we used an independent cohort of 792 non-melanoma cancer patients treated with ICIs. Consistent with prior studies, TMB-high (>10 mutations/Mb) was significantly associated with improved overall survival (hazard ratio (HR) [95% CI] = 0.72 [0.53, 0.98]) in melanoma. However, TMB-high was not associated with cirAE development (HR = 0.92 [0.69, 1.22]). Binary logistic regression revealed that somatic mutations in PRKCI (OR = 2.76 [1.27, 6.33]), STAG2 (OR = 2.25 [1.09, 4.80]), and CXCR4 (OR = 2.56 [1.02, 6.80]) were associated with increased odds of cirAE. Furthermore, time-to-event Cox regression identified that somatic mutations in PRKCI, STAG2, and CXCR4 as well as five additional genes (MEN1, AKT3, FANCG, DAXX, H3F3B) were significantly associated with increased risk of cirAE development (nominal p-values<.05). Mutations in CXCR4 replicated in the validation cohort as significantly associated with time to cirAE (HR = 4.02 [1.22, 13.21]) adjusting for cancer type, ICI type, and demographics. Of the CXCR4 mutations identified in patients with cirAE, 5/15 (33%) localized to the C-terminus, were predicted deleterious by SIFT and PolyPhen2, and altered key residues known to be involved in CXCR4 degradation, suggesting a mechanistic link between CXCR4 gain-of-function mutations and increased risk of cirAE. We identified somatic mutations in several genes as significant predictors of cirAE development in melanoma. The association between mutations in CXCR4 and cirAE was replicated in a pan-cancer validation cohort, providing mechanistic insight into cirAE development across cancers. Citation Format: Ninghui Hao, Jenny Lai, Crystal Chang, Ahmad Rajeh, Chuck Lin, Cameron Moseley, Arjun Mahajan, Matthew Tran, Coleen Valery, Christopher J. Thang, Guihong Wan, Alexander Gusev, Yevgeniy R. Semenov. Somatic variant predictors of cutaneous immune-related adverse events in cancer patients treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5802.