PD.01.01 Acquired EGFR Resistant Mutations and Co-mutations in Tumors Of Non-small Cell Lung Cancer Patients Treated With Tyrosine Kinase Inhibitors (TKI)

Abstract

Introduction: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) treated with EGFR mutant non-small cell lung cancer (NSCLC), is inevitable. Mechanisms include acquired EGFR mutations (718V, c797x, 724s, 721s or T790M); amplifications in MET, ERBB2, and PIK3CA; gene fusions; and histological transformation. We present the prevalence of resistance mutations in the largest reported cohort of EGFR mutant NSCLC. Methods: Tumors were submitted for next generation sequencing (592 Genes) and whole exome sequencing (NovaSeq) to Caris (Phoenix, AZ). PD-L1 expression was tested by IHC using 22C3 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. Pts information was obtained from insurance claims data. Results: 27,848 NSCLC tumors were evaluated and 3,223 (12%) had an EGFR mutation. We found 60 resistance mutations: 790M (n=30, 0.9%), 797S (n=38, 1.2 %), 718L (n=11, 0.3%), 724S (n=7, 0.2%) and 721S (n=4, 0.1). Table 1 describes: frequencies, PD-L1 expression and co-mutations. TMB-H (>=10) was found in 12.5% of the tumors and dMMR/MSI-H in 1.8%. Prevalent co-alterations were TP53 (54%), gLOH (28%), CTNNB1 (19%), NFKB1A (13%), APC (10%), PIK3CA (11%), SMAD4 (9%). Fifteen additional co-mutations were observed in less than 7% of pts. Of the 30 with T790M mutations, in addition to TP53 mutations, other co-mutations included PIK3CA (14%) and CTNNB1 (17%). In T797 mutations, prevalent co-mutations were T790M (68%) TP53 (53%), CTNNB1 (22%), APC (16%) and PIK3CA (11%). L718 mutations co-occurred with either L858R (6/11), exon 19 (3/11) or T790M mutations (3/11); 5/11 pts were treated with osimertinib before developing L718V. G724 mutations were found in 7 pts (0.02%) and G721 mutations in 4 pts (0.01%). Discussion: Acquired resistance in EGFR mutant NSCLC remains low due to lack of testing at resistance. While T790M and C797S mutations are well described, we document L718V mutations in osimertinib-treated pts with an original L858R. We need to increase NGS in pts who develop resistance because it is very heterogeneous and will help to develop new TKIs. [Formula presented]