Background: KRAS mutations in non-small cell lung cancer (NSCLC) still remain therapeutically untargetable. Assuming that these mutations are not mutually exclusive with other driver aberrations, we set out this study in order to describe and analyze co-occurring mutations and their potential therapeutic impact. In a subset of patients with co-occuring driver mutations, we performed additionally whole-exome sequencing (WES) to define clonal and evolutional status of the mutations. Results were compared with data from The Cancer Genome Atlas' (TCGA) for NSCLC. Methods: In a timeframe of 20 months, 4507 patients of a local screening initiative (Network Genomic Medicine Lung Cancer) were analyzed using next-generation parallel sequencing (NGS). The NGS panel consisted of 102 amplicons and 14 genes: KRAS, PIK3CA, BRAF, EGFR, ERBB2, NRAS, DDR2, TP53, ALK, CTNNB1, MET, AKT1, PTEN and MAP2K1. In subsets of patients, fluorescence in-situ hybridization (FISH) was performed for MET, FGFR1, and HER2 amplification and for RET, ALK and ROS1rearrangements. Clinical parameters, therapy, survival and smoking status were also collected. Results: We identified 1207 patients (26.8%) harboring a KRAS mutation, whereof 1080 patients (89.5%) underwent the complete diagnostic panel. The most common mutation was G12C accounting for 41.2%. In a total of 308 patients (28.8%) additional aberrations could be detected, including MET (prevalence 15.3%), FGFR1 (5.0%) and HER2 (12.7%) amplification and mutations in PIK3CA (3.4%), DDR2 (4.4%), PTEN (1.9%), CTNNB1 (1.7%), BRAF (1.3%) and EGFR (1.4%). Less frequently, mutations within NRAS, AKT1, ALK, MET, and MAP2K1 could be detected. 459 patients (42.9%) had co-occurring TP53mutations.. WES on selected cases confirmed the presence of these mutations. Conclusions: To our knowlege our data represent the largest analysis of co-occuring mutations in KRAS- mutated NSCLC. They show that KRAS-mutated NSCLC represents a heterogenous group of tumors with a substantial portion harboring a wide spectrum of additional targetable mutations. Further studies will show whether these findings translate into new therapeutic options in KRAS-mutated NSCLC.