Somatic mutations predict immune-related adverse events (irAEs) and survival following CTLA4 blockade in melanoma patients.

Abstract

e21584 Background: Predicting immune-related adverse events (irAEs) resulting from immune checkpoint inhibitors (ICIs) as well as the likelihood of clinical benefit is an area of great interest. irAEs have been associated with clinical outcome measures and we were interested in examining somatic mutations that may correlate with irAEs and subsequently with relapse free survival (RFS) and overall survival (OS). Methods: Our irAEs of interest for this analysis were rash and colitis based on prior data and these were tested for association with RFS and overall OS. Nonsynonymous somatic mutations were identified utilizing tumor and matched blood samples from 22 metastatic melanoma patients treated with neoadjuvant ipilimumab. Whole exome sequencing was performed using the SOLiD 5500 Next-Generation Sequencing platform. Somatic mutations were identified by subtraction of germline variants. Total mutational burden was assessed, and individual mutations were correlated with irAEs and with clinical outcome. Results: MUC16 was the most commonly mutated gene (82%). Of notable known oncogenic mutations, BRAF was the most common (50%) followed by NRAS (23%). Among known oncogenic signaling pathways, enrichment was most common in RTK-RAS (58%), followed by NOTCH and WNT. Development of colitis showed a strong trend in association with RFS. Development of rash indicated a similar trend. 20 different statistically significant mutations (p < 0.05) were identified among patients with colitis and these were also associated with OS and RFS. Notably, PTPRO mutation status (known to antagonize PDL1 expression) appeared protective against colitis and associated with worse RFS and OS. Similarly, ADGB mutation was significantly associated with developing rash and also associated with improved RFS and OS. Correcting for TMB in a multivariate model confirmed the associations. Conclusions: Somatic mutations were found to be associated with the irAEs of rash and colitis and with clinical outcome following ipilimumab treatment of melanoma. Our findings warrant further investigation and validation in independent cohorts.