5121 - Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study

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=10; C797G n=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=3; 4%), KRAS (n=1; 1%) and PIK3CA (E545K, n=1; 1%), and oncogenic fusion mutations in FGFR3, RET and NTRK (n=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.

Clinical trial identification

ClinicalTrials.gov NCT02151981

Editorial Acknowledgement

We thank Natalie Griffiths, PhD, from iMed Comms, who provided medical writing support funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (ismpp.org/gpp3).