Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC

In the phase III AURA3 trial, osimertinib had superior efficacy compared with platinum-based doublet chemotherapy (CT) in patients with EGFR^T790M-positive advanced NSCLC, whose disease progressed on or after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. During ESMO 2018 results were presented of an analysis looking for acquired mutations in plasma circulating tumour DNA (ctDNA) of patients whose disease progressed on osimertinib during AURA3. A diverse mixture of resistance mechanisms was detected, with MET amplification and the EGFR^C797S mutation as the most common genetic aberrations. Loss of the EGFR^T790M mutation was seen in approximately half of the patients and was associated with a shorter progression-free survival (PFS).

In the AURA3 study, a total of 419 patients with advanced NSCLC harbouring an EGFR^T790M mutation, whose disease had progressed on first-line EGFR-TKI therapy, were randomized in a 2:1 ratio 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. In the context of an exploratory analysis to investigate mechanisms of resistance to osimertinib, these plasma samples were analysed by next generation sequencing (NGS) using the Guardant360 assay (73 gene panel). Of note, this type of NGS analysis only picks up genomic alterations that are detectable in ctDNA and will not identify non-genetic resistance mechanisms (e.g. protein expression changes, SCLC transformation, etc.). In addition, amplification events are often underrepresented in this type of plasma analyses.

Among the 279 patients who were randomized to the osimertinib treatment arm, paired plasma samples were available from 83 (30%) patients who had progressed and/or discontinued treatment. In total, 73/83 (88%) patients had baseline detectable ctDNA EGFR mutations (EGFR^L858R, exon 19 deletion or EGFR^T790M) and were evaluable for this analysis. Among these 73 patients, 36 (49%) had no detectable EGFR^T790M at the time of disease progression. Acquired EGFR mutations were observed in 21% of patients, most commonly EGFR^C797S (10/73; 14%). All patients with acquired EGFR mutations retained EGFR^T790M in their disease progression, or discontinuation sample. MET amplifications were observed in approximately 19% of patients at disease progression. In the samples displaying a MET amplification, there was an equal split in patients who lost or maintained their EGFR^T790M status at disease progression. HER2 amplifications were reported in 5% of patients, while in 3 (4%) patients an amplification of the PI3KCA gene was seen. Oncogenic fusions involving FGRF3, RET and NTRK, were identified in 3% of patients and co-occurred with an EGFR^C797X mutation and a MET amplification. Cell cycle gene alterations were acquired in 12% of the samples. In slide 3 attached to this report, a schematic overview of the acquired resistance mechanisms post osimertinib is depicted. The numbers for each resistance event were too low to make any correlation with PFS. However, the investigators did show that loss of EGFR^T790M was associated with a slightly shorter median PFS (median PFS for EGFR^T790M lost versus retained: 5.54 versus 7.06 months).

In summary, a diverse mixture of resistance mechanisms to osimertinib was detected and the nature of these mechanisms was in line with previous reports. Acquired EGFR mutations and MET amplification were the most common events with EGFR^C797X being the most common acquired EGFR mutation. Interestingly, in one fifth of the patients in this analysis more than 1 resistance related alteration was observed. Analyses like this are important as they increase the understanding of resistance mechanisms in the first and second-line setting and could ultimately help to define appropriate combination therapies.

Reference

Papadimitrakopoulou V, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Presented at ESMO 2018; Abstract LBA51