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Background Predicting the risk of immune related adverse events (irAEs) including dermatitis following exposure to immune checkpoint inhibitors (ICI) continues to be an urgent need and may have implications regarding irAE management and prediction of clinical benefits.Methods We conducted genome-wide genotyping on samples from 744 patients with melanoma enrolled in ECOG-ACRIN E1609 trial ( NCT01274338)1 that tested ipilimumab, for which patients provided IRB-approved consent (Advara IRB# Pro00014875). We used the Illumina Infinium Global Screening Array v.3.0 + Multi-Disease BeadChip with 730059 custom markers. Genotypes were called using Illumina Genome Studio 2.0 and IAAP CLI v1.1.0, quality controlled, and harmonized with the 1000 Genomes Phase 3 (1KGP3) references. We used the Michigan Imputation Server 2, pipeline v2.0.6, to impute genotypes against the hrc-r1.1 reference panel. We applied logistic regression implemented in plink (v2.00a4LM glm with firth fallback) to estimate associations between inherited genetic markers and the occurrence of dermatitis in our patient cohort; models included inferred genetic ancestry proportions on the EUR axis as a covariate. We also calculated all polygenic risk scores (PRS) for dermatitis listed in PGS-Catalog v20240318.Results We examined 11 distinct PRSs previously reported to be associated with dermatitis syndromes (PGS000927, PGS000944, PGS002323, PGS002363, PGS002395, PGS002444, PGS002493, PGS002542, PGS002591, PGS002640, and PGS002689). None were significantly associated with the occurrence of ICI-mediated dermatitis in our study when examined across irAE grades (Kruskal-Wallis p>0.05) or when irAE grades were dichotomized (Wilcoxon p>0.05). From our genome-wide association analysis, we identified 2 independent SNPs that were significantly associated with dermatitis irAE outcomes [SNP#1 on chromosome 15 (OR=0.61, p=3.8e-6) and SNP#2 on chromosome 6 (OR=0.61, p=7.8e-6)]. When combined using log(OR) as weights, these SNPs were significantly associated with the severity of the dermatological irAE grades, both across irAE grades (Kruskal-Wallis p=4.4e-9) and when dichotomized as any dermatological irAE vs. none (Wilcoxon p=1.2e-10). In multivariable survival analysis adjusting for primary status (known, unknown) and sex (male, female), the combination of the 2 SNPs trended towards an association with overall survival (p=0.12) and relapse free survival (p=0.13).Conclusions Our analysis generated a novel PRS that predicts ICI-mediated dermatological irAEs in the context of a U.S. Intergroup phase 3 trial. Further analyses including validation are ongoing. In parallel, 11 distinct PRSs previously reported for dermatitis syndromes were not found to be significantly associated with the occurrence of dermatitis in this ICI setting.Reference Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. doi: 10.1200/JCO.19.01381. Epub 2019 Dec 27. PMID: 31880964; PMCID: PMC7030886.