Abstract 1352: Genetic susceptibility to immune-related adverse events among melanoma patients treated with ipilimumab
Authors: Pluta John , Qian Lu , D'Andrea Kurt , Duan Chunzhe , Weathers Benita , Wind-Rotolo Megan , Kanetsky Peter , Nathanson Katherine 
Published: July 2021

Abstract
Background: Ipilimumab is an immune checkpoint inhibitor used to treat melanoma. Although the development of immune-related adverse events (irAEs) among patients treated with ipilimumab is well documented, little is known about factors that may increase risk of irAEs. We conducted a genome-wide association study (GWAS) to examine the genetic susceptibility to irAEs in response to ipilimumab monotherapy.
Methods: In partnership with Bristol Myers Squibb BMS, extant genotype data and clinical information were obtained on melanoma patients treated with ipilimumab monotherapy from three clinical trials. Only patients who were treatment naïve were included in our analyses. We defined our outcome as the occurrence of a serious irAE, grade 3 or higher. We first analyzed data from 294 subjects, 79 with severe irAE, enrolled on CA184-169 for whom genotyping was completed using the Affymetrix 6 array. After appropriate quality control, SNP associations were determined using logistic regression models that were adjusted for ancestry, ECOG status, ipilimumab dosage (3 mg/kg vs 10 mg/kg), and number of doses (&lt;4 vs 4+). Next, we analyzed data from 175 subjects, 63 with severe irAE, enrolled on CA209-067 or CA209-069 for whom genotyping was completed using the Illumina MegaEX array; and SNP associations were similarly determined after adjustment for ancestry, trial, and number of doses (&lt;4 vs 4+). Summary statistics from the two analyses were combined using a fixed-effect meta-analysis. Because of the small sample size, we used a sub-genome-wide significance level of 1 × 10-5 to indicate potentially important findings.
Results: The most statistically significant marker (rs55981606, p=1.39 × 10-7) and a second independent marker (rs72712605, p=6.33 × 10-6) mapped to a non-coding region on chromosome 9. We identified a marker (rs65949485, p = 9.38 × 10-6) intragenic between the SHQ1 and GXYLT2 genes, both of which are involved in the Notch signaling pathway. Markers proximal to NR2F2 (rs13270533, p=7.8 × 10-6) and within SAMD12 (rs13270533, p = 9.23 × 10-6) were also identified; the latter two genes have been implicated as being oncogenic. Additionally, we identified several markers implicating genes involved in inflammation, specifically macrophage activation, including TLE1 (rs3739581, p = 9.25 × 10-7), SLC16A4 (rs2271885, p=9.23 × 10-6) and CYP2J2 (rs427970, p=2.03 × 10-6).
Conclusions: Results from our meta-analysis suggest that genes related to inflammation processes and those with known contributions to oncogenesis may play a role in the development of severe irAEs resulting from ipilimumab monotherapy. If further validated, these findings may provide the foundation to advance models to discriminate patients with a high likelihood of suffering irAE allowing for heightened surveillance of symptom onset or joint decision making for alternative therapies.
Citation Format: John Pluta, Lu Qian, Kurt D'Andrea, Chunzhe Duan, Benita Weathers, Megan Wind-Rotolo, Peter Kanetsky, Katherine Nathanson. Genetic susceptibility to immune-related adverse events among melanoma patients treated with ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1352.