BACKGROUND: Fusion of the gene resulting in clinically significant Genomic Alteration (GA) occur in 1-2% of NSCLC in the United States and has emerged as a major target for inhibitors which are first line treatment options in the Stage 4 setting. fusions have also been well-described as acquired resistance mutations in cases of -driven NSCLC treated with anti- tyrosine kinase inhibitors including erlotinib and osimertinib. The aim of this study was to determine whether fusion positive () NSCLC represents a unique histologic subtype of the disease with a unique genomic profile. METHODS: We selected 503 of 72,596 (0.7%) total NSCLC that were reported as from the Foundation One database. The cases were centrally evaluated for predominant histology and underwent hybrid capture based CGP to evaluate diverse GA. Cases with mutations were excluded. PD-L1 expression was determined by Immunohistochemistry (IHC) (Dako 22C3) with Tumor Proportion Score (TPS) ≥50% = high expression. For statistical comparisons, the false discovery rate was corrected using Benjamini/Hochberg adjustment. RESULTS: Potentially targetable GAs found less frequently in the group included , AND . The presence of and gene signatures were also lower in frequencies in the NSCLC cases. was the only GA found to be higher in the group. While markers predictive of checkpoint therapy response including TMB high level was more frequent in the cases, PD-L1 high expression was more in samples. Surgical pathology analysis revealed that the high grade solid non-acinar pattern at 32% was the most frequent histologic subtype. CONCLUSIONS: NSCLC features a unique genomic signature which can further impact therapy selection. With recent expanded approval of more specific RET kinase targeting inhibitors (selpercatinib and Pralsetinib) in the pan-cancer treatment setting, further study of NSCLC histology and genomic/biomarker status appears warranted.