Prevalence and molecular correlates of acquired <i>EGFR</i> 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 <i>EGFR</i> mutations, acquired resistance is expected. We aimed to determine the prevalence and molecular correlates of <i>EGFR</i> resistance mutations in a large, real-world cohort of <i>EGFR</i>-mutated NSCLC. NSCLC tumors (<i>N</i> = 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. <i>EGFR</i> sensitizing mutations (exon 19 deletions, L858R mutations) were present in 3,885 patients with NSCLC, and <i>EGFR</i> 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 <i>TP53</i> (50%), PD-L1 positivity (40%), gLOH (20%), and <i>CTNNB1</i> (23.2%). L718 mutations predominantly co-occurred with L858R without T790M, and 9/16 developed post-osimertinib treatment. Acquired resistance mutations in <i>EGFR</i>-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.