Background: EGFR mutations are present in more than 10% of patients (pts) with NSCLC in the US. While EGFR with tyrosine kinase inhibitors (TKIs) are effective, acquired resistance is expected. Known mechanisms include acquired EGFR mutations (e.g. 718V, c797x, 724s, 721s or T790M); copy number amplifications in MET, ERBB2, and PIK3CA; gene fusion events; and histological transformation. We herein present the prevalence of resistance mutations in the largest reported cohort of EGFR mutant NSCLC. Methods: Non-small cell lung cancer (NSCLC) tumor samples were submitted to Caris Life Sciences (Phoenix, AZ) for NextGen Sequencing (NextSeq, 592 Genes) and whole exome sequencing (NovaSeq, WES). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff >1). TMB was measured by totaling somatic mutations (TMB-high cut-off > 10 mutations per MB), genomic loss of heterozygosity (gLOH) was determined by WES. Patient treatment information was obtained from insurance claims data. Results: A total of 27,848 NSCLC tumors were evaluated and 3,223 (12%) had a EGFR sensitizing mutations. We found 60 tumors with common missense resistance mutations: 790 (n = 30, 0.9%), 797 (n = 38, 1.2 %), 718 (n = 11, 0.3%), 724 (n = 7, 0.2%) and 721 (n = 4, 0.1). Table 1 describes the frequencies, PD-L1 expression and the most common co-mutations. TMB-H (> = 10) was found in 12.5% of the tumors and dMMR/MSI-H in 1.8%. The most prevalent co-alterations were TP53 54%), gLOH (28%), CTNNB1 (19%), NFKB1A (13%), APC (10%), PIK3CA (11%), SMAD4 (9%) and other 15 co-mutations in less than 7% were seen. In the 30 T790M mutants, in addition to TP53 mutations, other prevalent co-mutations were PIK3CA (14%) and CTNNB1 (17%). In 797-mutant tumors, in addition to T790M, the most prevalent co-mutations were TP53 (53%), CTNNB1 (22%), APC (16%) and PIK3CA (11%). L718 mutations co-occurred with either L858R (8/11), exon 19 (3/11) or T790M mutations (3/11). G724 mutations were found in 7 patients (0.02%) and G721 mutations in 4 patients (0.01%). Conclusions: Acquired resistance in EGFR mutant NSCLC is very heterogeneous and their frequency is still low most likely due to lack of enough sequencing of EGFR resistant tumors. While T790M and C797S mutations are well described, this report also notes a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the NGS evaluation of patients with resistant EGFR mutant lung cancers.