Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer

Abstract

In the phase III FLAURA study (NCT02296125), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib provided superior progression-free survival versus comparator EGFR-TKIs in patients with NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to first-line osimertinib in patients from the FLAURA trial. Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted.