Introduction: EGFR alterations have important therapeutic implications in lung cancer (LCa). The incidence of these alterations, their subtypes, and co-mutational status is well described in Caucasian and East Asian but not in African American populations. Using the Tempus database, we analyzed real-world data from EGFR mutant LCas across races, assessing alteration subtypes and co-mutational profiles.

Methods: De-identified records with primary LCa diagnosis tested via Tempus xT assay and had ≥1 pathogenic EGFR mutation (SNVs, CNAs, or fusions) were identified. Race was determined based on recorded clinical records, and stratified as Caucasian (CA), African American (AA), Asian Pacific Islander (API), unknown or other. Somatic pathogenic co-mutations were restricted to genes >5% frequency ≥1 race. Data is described using N(%) or median and IQR. Comparisons were made by Chi-squared/Fisher’s Exact or Kruskal-Wallis tests. Bonferroni or FDR corrections were applied to pairwise comparisons.

Results: Of 17,482 LCa samples with prior Tempus xT assay performed on the most recently received tumor specimen, 55.1% were CA, 7.7% AA, 2.5% API, 3.0% other, and 31.7% unknown. Pathogenic EGFR alterations occurred in 8.9% of CA, 7.8% of AA, 39.5% of API, 15.1% of other, and 11.9% unknown. In the EGFR altered population, average age at diagnosis was 68 (60, 75; p=0.065), 63% female, and 96% had no history of tyrosine kinase inhibitor (TKI) therapy prior to sequencing. Majority had advanced stage disease and were diagnosed with adenocarcinoma. Frequency of exon 19 deletions differed across races (p=0.017), with the highest frequency in “other” races. L858R mutations also differed (p < 0.001) and was significantly higher in CA versus AA (p=0.034) and API versus CA (p=0.006). EGFR CNVs differed across races (p<0.001), with frequencies highest in AA. No statistically significant differences were observed for T790M or, exon 20 insertions. Lastly, KMT2C co-mutations significantly differed (q=0.003), with 13% AA, 3% CA and 4%, API. Similarly, GLI1 differed across races, with highest frequency in AA (5.8%). There was no difference in TP53, RB1, or NTRK2/3 mutations observed.

Conclusions: Significant differences in the prevalence of EGFR alterations were observed across races, with specific co-mutations like KMT2C and GLI1 occurring more frequently in AA compared to CA and API patients. KMT2C may be linked to higher TMB and immunotherapy response, while GLI1 has been shown to be involved in erlotinib resistance. Variabilities in alterations across races may inform more effective treatment strategies for LCa patients.

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