Background: Next-generation sequencing (NGS) to detect targetable oncogenic driver mutations is standard of care in non-small cell lung cancer (NSCLC). However, the interpretation and clinical impact of copy number amplifications (CNA) of driver genes is less clear. ERBB2, KRAS and MET are oncogenic drivers with intersecting resistance mechanisms and evolving therapeutic landscapes. We examined the overlap between other oncogenic drivers and CNA of these genes, and the association of CNA with overall survival (OS), in a cohort of patients with NSCLC. Methods: NGS of DNA (592 genes or WES)/RNA (WTS) was performed for 5870 consecutive lung adenocarcinoma tumors submitted to Caris Life Sciences (Phoenix, AZ). The copy number of each exon was determined by calculating the average depth of the sample along with the sequencing depth of each exon. Driver oncogenes (Driver+/-) were defined as pathogenic fusions in ALK, NTRK (1,2 and 3), RET and ROS1 or pathogenic SNVs/indels in ALK, BRAF, EGFR, ERBB2, KRAS, MET. Tumor mutational burden high (TMB-H) was defined as 10 mutations per MB. The χ² test was applied as appropriate (p < .05). Results: The cohort was 55% female; median age was 69 years (range 24-89) and similar across all cohorts. Incidence of CNA at different amplification thresholds was correlated with oncogene drivers. At CNA ≥6 for ERBB2 and KRAS, but CNA ≥4 for MET, a significant tendency for mutual exclusivity with driver mutations was observed (log2 odds ratio ERBB2: -3.1, KRAS: -1.1,MET: -2.2, all p< .001). Tumors meeting these thresholds were designated CNA-High (Gene-H), versus CNA-Low (Gene-L). Only one tumor harboured two CNA-H genes (KRAS and MET). Independent of CNA status, the TMB-H frequency was decreased in Driver+ tumors (27% vs 52% in Driver-, p< .001). CNA-H tumors were associated with decreased OS (compared to CNA-L); for ERBB2-H, hazard ratio (HR) 1.74 (95% CI 1.44-2.10, p < .001), for KRAS-H HR 1.29 (1.16-1.65, p< .001), and for MET-H HR 1.46 (1.28-1.68, p < .001). Similar results were observed when stratified by driver mutation status (Table), with the exception of KRAS/Driver- tumors. Conclusions: These data suggest tumors with high CNA of ERBB2, KRAS and MET represent clinically distinct entities and are significantly less likely to harbour concurrent driver oncogenes. The association between increased copy number and worse OS suggests amplified tumors are an important area for therapeutic development. Overall survival (collection to last contact) for ERBB2, KRAS and MET CNA-High versus CNA-Low tumors, by Driver mutation status.