Mutated Processes Predict Immune Checkpoint Inhibitor Therapy Benefit in Metastatic Melanoma

Immune Checkpoint Inhibitor (ICI) therapy has revolutionized treatment for advanced melanoma; however, only a subset of patients benefit from this treatment. Despite considerable efforts, the Tumor Mutation Burden (TMB) is the only U.S. Food and Drug Administration (FDA) approved biomarker for ICI treatment in melanoma. However, the mechanisms underlying TMB association with prolonged ICI survival are not entirely understood and may depend on numerous confounding factors. To identify more interpretable ICI response biomarkers based on tumor mutations, we trained classifiers using mutations within distinct biological processes. We evaluated a variety of feature selection and classification methods, and identified key mutated biological processes that provide improved predictive capability compared to the TMB. The top mutated processes identified are leukocyte and T-cell proliferation regulation; importantly, these processes demonstrate stable predictive performance across different data cohorts of melanoma patients treated with ICI. This study provides new methodology to construct biologically interpretable genomic predictors for ICI response with substantially improved predictive performance over the TMB.