BACKGROUND: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.
RESEARCH DESIGN AND METHODS: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.
RESULTS: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.
CONCLUSIONS: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.