In this cohort study of 3 groups of patients, including The Cancer Genome Atlas cohort with 10 195 patients across 30 solid tumor types, 56 patients with non–small cell lung cancer, and 145 patients with melanoma, MUC16 mutation was associated with greater response rates, prolonged overall survival, and genomic factors associated with ICI response, including tumor mutational burden and programmed cell death ligand–1 expression. Here, MUC16 is linked to lung cancer.