BACKGROUND: EGFR alterations have significant therapeutic implications in lung cancer (LCa), yet their prevalence and co-mutational patterns in African American populations remain understudied. This study analyzes EGFR-mutant LCa across races using the Tempus database. METHODS: De-identified records sequenced via Tempus xT assay, (595 to 648 gene DNA panel) were included if they had ≥ 1 pathogenic EGFR mutation (short variants (SVs), copy number amplifications (CNAs), or fusions). Race was determined based on recorded clinical records. Co-mutations were restricted to genes with ≥ 5% frequency in at least 1 race. Statistical analyses were performed using chi-squared tests with Bonferroni or false discovery rate adjustments for multiple testing. RESULTS: Among 17,482 LCa samples, EGFR alterations occurred in 8.9% of CA, 7.6% of BAA, 39% of API, 15% of other races, and 12% of unknown races. Exon 19 deletions (P = .017) and L858R mutations (P <
.001) varied by race, with higher L858R frequency in CA compared to BAA (P = .034) and in API compared to CA (P = .006). EGFR copy number variants (CNVs) were highest in BAA (P <
.001). TP53 alterations occurred at a higher frequency in patients with a history of smoking, those with high tumor mutational burden (TMB), and high PD-L1. KMT2C co-mutations were significantly more common in BAA (13%) compared to CA (3%) and API (4%) (q = 0.003). Similarly, GLI1 co-mutations were most frequent in BAA (5.8%) compared to 1.5% in CA and 0% in API patients (q = 0.025). CONCLUSIONS: EGFR mutation subtypes and co-mutations differ by race. KMT2C may influence TMB and immunotherapy response, while GLI1 is linked to TKI resistance. TP53 alterations were more commen in smokers, and patients with high PDL-1 and TMB, highlighting additional factors that drive tumors with these alterations.