mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of mutations, patients with -mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with -mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. We identified patients with advanced -mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Among 330 patients with advanced -mutant lung cancers, the most frequent co-mutations were found in (42%), (29%), and / (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in / [HR, 1.96; 95% confidence interval (CI), 1.33-2.92; ≤ 0.001]. (HR, 1.3; = 0.22) and (HR 1.11, = 0.58) co-mutation statuses were not associated with survival. Co-mutation in / was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59; = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11; = 0.003). Among people with -mutant advanced NSCLC, , and / are the most commonly co-occurring somatic genomic alterations. Co-mutation of and / is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy. .