5005 - Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study

Background

In the Phase III FLAURA study (NCT02296125), osimertinib showed superior efficacy compared with standard of care (SoC) EGFR-TKIs in patients (pts) with previously untreated EGFRm advanced NSCLC. Here, we report preliminary data on mechanisms of acquired resistance to osimertinib in pts who progressed during the FLAURA study.

Methods

Pts with previously untreated EGFRm (tissue, ex19del/L858R) advanced NSCLC (N=556) were randomised 1:1 to osimertinib 80 mg once daily (QD; n=279) or SoC EGFR‑TKI (n=277, gefitinib 250 mg QD or erlotinib 150 mg QD). Paired plasma samples were collected at baseline and following RECIST progression and/or treatment discontinuation up to March 2018. Plasma samples were analysed using next generation sequencing (NGS, Guardant Health; Guardant360 73 gene panel or Omni 500 gene panel).

Results

In the osimertinib and SoC EGFR-TKI arms, respectively, 113/279 (41%) and 159/277 (57%) pts had experienced a progression event and/or discontinued treatment and had paired plasma samples analysed by NGS. Only pts with detectable plasma EGFRm (ex19del/L858R) at baseline were evaluable for this analysis: 91/113 (81%; osimertinib) and 129/159 (81%; SoC). In the osimertinib arm, there was no evidence of acquired EGFR T790M and the most common acquired resistance mechanism detected was MET amplification (amp; 14/91; 15%), followed by EGFR C797S mutation (6/91; 7%); other mechanisms included HER2 amp, PIK3CA and RAS mutations (2–7%). In the SoC arm, the most common resistance mechanisms were T790M mutation (60/129; 47%), MET amp (5/129; 4%) and HER2 amp (3/129; 2%).

Conclusions

In this paired sample preliminary analysis of a subpopulation of pts (with detectable baseline plasma EGFRm) who had experienced disease progression and/or discontinued treatment, heterogeneous resistance mechanisms were detected with first-line osimertinib, with MET amplification and EGFR C797S mutation being the most commonly observed. In line with previous analyses, T790M was acquired in approximately 50% of SoC-treated pts, and none of the osimertinib‑treated pts; no unexpected resistance mechanisms were observed in osimertinib-treated pts. Exploration into novel acquired mutations is ongoing.

Clinical trial identification

NCT02296125

Editorial Acknowledgement

We thank Ellen Maxwell, PhD, from iMed Comms, who provided medical writing support funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines ().