Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study

Abstract

Background: In the Phase III AURA3 trial (NCT02151981), osimertinib had superior efficacy compared with platinum-based doublet chemotherapy (CT) in patients (pts) with T790M-positive advanced NSCLC, whose disease progressed on or after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. Here we report the ctDNA genomic profile of pts with T790M-positive advanced NSCLC, whose disease progressed on osimertinib treatment during the AURA3 trial. Methods: Pts with EGFR T790M advanced NSCLC, whose disease had progressed on first-line EGFR-TKI therapy, were randomized 2:1 to osimertinib (80 mg once daily) or platinum-based doublet CT. Paired plasma samples were collected at baseline and following disease progression and/or treatment discontinuation. Plasma samples were analyzed by next generation sequencing (NGS; Guardant Health, Guardant360, 73 gene panel). Results: Among 279 pts randomized to the osimertinib treatment arm, paired plasma samples were available from 83 (30%) pts who had progressed and/or discontinued treatment (PD/DC). 73/83 (88%) pts had baseline detectable ctDNA EGFR mutations (L858R, exon 19 deletion or T790M) and were evaluable for this analysis. Among these 73 pts, 36 (49%) had no detectable T790M at PD/DC, and 11 (15%) acquired EGFR secondary mutation in C797 (C797S n ¼ 10; C797G n ¼ 1). Amplification of MET, HER2, and PIK3CA were detected in 14 (19%), 4 (5%), and 3 (4%) samples, respectively. Other mechanisms of acquired resistance included mutations in BRAF (V600E, n ¼ 3; 4%), KRAS (n ¼ 1; 1%) and PIK3CA (E545K, n ¼ 1; 1%), and oncogenic fusion mutations in FGFR3, RET and NTRK (n ¼ 3; 4%). Conclusions: In this preliminary analysis from AURA3 of paired plasma samples from pts with detectable baseline plasma EGFR mutations and at PD/DC on osimertinib treatment, a diverse mixture of resistance mechanisms were detected, with MET amplification and EGFR C797S most common. No unexpected resistance mechanisms were observed in these second-line osimertinib-treated pts. Understanding resistance mechanisms in the first and second-line settings will help define appropriate combination therapies.