Abstract
After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients’ samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third-generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC.
Highlights
EGFR tyrosine kinase inhibitors (TKIs) have exhibited clinically significant therapeutic responses in non-small cell lung cancer (NSCLC) patients with tumors that harbor the most frequent EGFR driver mutations [1,2,3]
We obtained the clinical history of nine patients and confirmed that all nine had received a first or second-generation EGFR TKI followed by a third-generation TKI (Fig 1A and 1B and Table 1 and S1 File)
comprehensive genomic profiling (CGP) of tissue after relapse on firstand second- generation EGFR TKI was performed on patients 1, 6, and 9 and found the original EGFR driver mutation (Table 2) in addition to a T790M mutation
Summary
EGFR tyrosine kinase inhibitors (TKIs) have exhibited clinically significant therapeutic responses in non-small cell lung cancer (NSCLC) patients with tumors that harbor the most frequent EGFR driver mutations [1,2,3]. These clinical responses are often short lived, and patients commonly relapse after acquiring an EGFR T790M mutation [4]. The most frequent mutations in EGFR that cause resistance to third-generation TKIs substitute the cysteine at codon 797 in exon 20, which prevents covalent binding [7]. Several mutations in other exons of EGFR have been recently identified to confer third generation EGFR-TKI resistance (L718/G719) [9]
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