Effects of Co-occurring Genomic Alterations on Outcomes in Patients with <i>KRAS</i> -Mutant Non–Small Cell Lung Cancer

Abstract

<b>Purpose:</b><i>KRAS</i> mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of <i>KRAS</i> mutations, patients with <i>KRAS</i>-mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with <i>KRAS</i>-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy.<b>Experimental Design:</b> We identified patients with advanced <i>KRAS</i>-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.<b>Results:</b> Among 330 patients with advanced <i>KRAS</i>-mutant lung cancers, the most frequent co-mutations were found in <i>TP53</i> (42%), <i>STK11</i> (29%), and <i>KEAP1</i>/<i>NFE2L2</i> (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in <i>KEAP1</i>/<i>NFE2L2</i> [HR, 1.96; 95% confidence interval (CI), 1.33-2.92; <i>P</i> ≤ 0.001]. <i>STK11</i> (HR, 1.3; <i>P</i> = 0.22) and <i>TP53</i> (HR 1.11, <i>P</i> = 0.58) co-mutation statuses were not associated with survival. Co-mutation in <i>KEAP1</i>/<i>NFE2L2</i> was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04-2.59; <i>P</i> = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55-8.11; <i>P</i> = 0.003).<b>Conclusions:</b> Among people with <i>KRAS</i>-mutant advanced NSCLC, <i>TP53, STK11</i>, and <i>KEAP1</i>/<i>NFE2L2</i> are the most commonly co-occurring somatic genomic alterations. Co-mutation of <i>KRAS</i> and <i>KEAP1</i>/ <i>NFE2L2</i> is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy. <i>Clin Cancer Res; 24(2); 334-40. ©2017 AACR</i>.