Prevalence and molecular correlates of acquired EGFR resistance mutations in non-small cell lung cancer (NSCLC).

While EGFR tyrosine kinase inhibitors (TKIs) are effective in treating patients with non-small cell lung cancer (NSCLC) with EGFR mutations, acquired resistance is expected. We aimed to determine the prevalence and molecular correlates of EGFR resistance mutations in a large, real-world cohort of EGFR-mutated NSCLC. NSCLC tumors (N = 46,505) were profiled by next-generation sequencing (NGS) and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Patient treatments and outcomes were obtained from insurance claims data. EGFR sensitizing mutations (exon 19 deletions, L858R mutations) were present in 3,885 patients with NSCLC, and EGFR resistance mutations (C797, T790M, L718, G724, G721) in 71 patients; 58 patients had both sensitizing and resistance mutations. Among tumors with resistance mutations, the most prevalent co-alterations were TP53 (50%), PD-L1 positivity (40%), gLOH (20%), and CTNNB1 (23.2%). L718 mutations predominantly co-occurred with L858R without T790M, and 9/16 developed post-osimertinib treatment. Acquired resistance mutations in EGFR-mutant NSCLC have a low observed frequency among molecularly-profiled tumors, possibly due to infrequent re-testing of resistant tumors. While T790M and C797S mutations are well-described, we also observed a significant number of L718 mutations in osimertinib-treated patients. These data support NGS evaluation of NSCLC that has become resistant to EGFR TKIs.