Several immune checkpoint inhibitors (ICIs) have been approved as first-line therapies for urothelial carcinoma (UC), and they have significantly improved clinical outcomes. Approximately 30% of patients with metastatic UC will respond to ICI immunotherapy. To identify genetic variables that can also benefit from ICIs, a recent study carried out whole-exome sequencing on tumor specimens taken from 88 patients with advanced UC treated with ICIs.
Several genetic factors, including ARID1A mutations, tumor mutational burden, intratumoral heterogeneity, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, and tumor cell purity were linked to progression-free survival and overall survival (OS) after ICI therapy. The neutrophil-to-lymphocyte ratio in patients was negatively associated with OS.
From these data, 4 molecular subtypes were defined as demonstrating differential sensitivity to ICIs. The subtypes were analyzed in the IMvigor210 trial and were found to receive clinical benefit from ICI treatment. The subtypes were also demonstrated to correlate with immune infiltration and inflammation in cohorts from IMvigor210 and The Cancer Genome Atlas Program.
These molecular subgroups have been shown to influence the benefit received from ICI therapy.