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Background: Although it was initially thought many driver alterations were mutually exclusive, it might not be so. These pathways may interact in a dynamic way. Whether these mutations are present in different cellular clones that emerge as a result of treatment pressure or they co-exist in the same cell is not yet fully clear. Methods: Between Nov. 2011Aug. 2014 clinical data from consecutive newly diagnosed lung cancer patients in our center were prospectively collected in a database. Mutational analysis of EGFR, KRAS, BRAF and PI3K as well as ALK rearrangement was determined in all metastatic Nsq-NSCLC. EGFR mutational analysis was carried out using next generation sequencing using the Cobas and Junior diagnostic method. KRAS, BRAF and Pi3Kanalysis was determined by next generation sequencing using Sequencing Multiplex and Junior System. ALK rearrangement was carried out by FISH and confirmed by IHQ (D5F3, Ventana diagnostics). Results: 327 patients were diagnosed with Nsq-NSCLC. 216 (66%) of the 327 patients had EGFR analysed, 132 (40.3%) KRAS, 128 (39.1%) BRAF, 122 (37.3%) PI3K and 126 (38.5%) ALK. Of the 216 with EGFR determination, 58 (26.8%) harbored EGFR mutations. Exon 19 deletions (44.4%), exon 21 mutations (L858R and L861Q-47.2%), exon 18 mutations G719A/C/S (13.8%). Fifty four (40.9%) KRAS mutations, 4 (3.1%) BRAF mutations, 12 (9.8%) PI3K mutations and 8 (6.3%) ALK rearranged .14 had coexistent mutations: 2 EGFR/ALK rearrangements , 9 EGFR/KRAS, 4 EGFR/PI3K, and 2 EGFR/BRAF. 3 patients had triple mutations in EGFR/BRAF/ALK, and 2 in EGFR/KRAS/PI3K. Conclusions: We show that these mutations may co-exist previous to receiving targeted therapy. Whether they represent a primary or acquired resistance to targeted therapy is important to determine (data to be presented on the tissue origin-primary tumor vs metastasis). In our series, 78.5% of the patients were heavy smokers. Most patients were not exposed to targeted therapy, but of those who were, most did not respond. Legal entity responsible for the study: