Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer

Background: KRAS mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC).  Despite the uniform presence of KRAS mutations, patients with KRAS-mutant NSCLC can have a heterogeneous clinical course. Since the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. Methods: We identified patients with advanced KRAS-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. Results: Among 330 patients with advanced KRAS-mutant lung cancers, the most frequent comutations were found in TP53 (42%), STK11 (29%), and KEAP1/NFE2L2 (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in KEAP1/NFE2L2 (HR 1.96, 95%CI 1.33-2.92, p=<0.001). STK11 (HR1.3, p=0.22) and TP53 (HR 1.11, p= 0.58) co-mutation status were not associated with survival. Co-mutation in KEAP1/NFE2L2 was also associated with shorter duration of initial chemotherapy (HR 1.64, 95% CI 1.04-2.59, p=0.03) and shorter overall survival from initiation of immune therapy (HR 3.54, 95% CI 1.55-8.11, p=0.003). Conclusions: Among people with KRAS-mutant advanced NSCLC, TP53, STK11, and KEAP1/NFE2L2 are the most commonly co-occurring somatic genomic alterations. Comutation of KRAS and KEAP1/ NFE2L2 is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum based chemotherapy, and survival from start of immune therapy.

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