Data from Advances in Precision Cancer Care - Curated by EPG Health - Last updated 23 October 2018

A Focus on LUNG 

Today’s report come from the Proffered paper session - NSCLC, metastatic, focusing on presentations LBA50 and LBA51 discussing mechanisms of acquired resistance to osimertinib from the phase III trials FLAURA and AURA3, respectively.

Scroll down for key insights from each presentation.

LBA50 | Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study

Dr Ramalingan presented preliminary results of a retrospective analysis of the phase III FLAURA trial looking at mechanisms of acquired resistance to first-line osimertinib in advanced EGFR mutated NSCLC. While acquired EGFR mutations (e.g. C797S) and amplifications of MET and HER-2 are known to be common resistance mechanisms to second-line osimertinib, there is very little information regarding potential mechanisms of resistance when this third-generation EGFR-TKI inhibitor is administered in the front-line setting.  

This study was conducted on paired blood samples from trial patients who progressed or discontinued treatment. Only those found to have sensitising EGFR mutations [exon 19 deletion or L858R] on the baseline blood sample were eligible and assessed with next-generation sequencing (Guardant Health) on circulating tumour DNA.  

129/277 (47%) patients in the control arm [gefitinib or erlotinib treatment] and 91/279 (33%) in the investigational arm [osimertinib] of the FLAURA trial were assessable. The study showed the most common mechanisms of resistance to erlotinib or gefitinib were T790M (47%), MET amplification (4%), PI3KCA mutations (3%), HER-2 amplification (2%) and CCDC6-RET fusion (2%).

In contrast, the most common mechanisms of resistance to osimertinib included MET amplification (15%), secondary EGFR mutations (10%, especially C797X 7%), cell cycle gene alterations (10%, including CDK4/6 amplification, 5%), PIK3CA mutation (7%), KRAS mutation (3%), BRAF V600E mutation (3%) and HER-2 amplification (2%). Of note, up to 14% of patients in the osimertinib arm were found to have multiple potential mechanisms of resistance. 

Dr Ramalingan concluded that, in contrast to patients who were treated with gefitinib or erlotinib, no T790M mutations occurred in patients who received osimertinib. Resistance to this third-generation EGFR-TKI is largely due to alternative genetic events, especially MET amplification and C797X mutations. 

Dr Ramalingan acknowledged this analysis could not address non-genetic mechanisms of resistance and amplification events may be underrepresented in blood samples. Therefore, results of similar analyses in tissue samples from other trials (e.g. ELIOS trial) are eagerly awaited. 

LBA51 | Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study

Dr Papadimitrakopoulou presented data from a retrospective circulating tumour DNA analysis of patients from the Phase III AURA3 trial. This analysis aimed to investigate the genomic profile of patients with T790M-positive advanced NSCLC, who progressed on osimertinib.

There is limited information on molecular determinants of resistance to osimertinib. Previous studies included small numbers of patients and analysed a mixture of tissue and plasma samples. According to these, EGFR C797S and MET amplification appear to be the most common genetic events leading to osimertinib resistance. 

This study was conducted on paired blood samples from trial patients who progressed or discontinued treatment. Only those patients who were found to have sensitising EGFR mutations (i.e. exon 19 deletion or L858R) and/or T790M mutation on the baseline blood sample were eligible and assessed with next-generation sequencing (Guardant360 assay, 73 genes) on circulating tumour DNA.  

24/140 (17%) patients in the control arm [platinum plus pemetrexed treatment] and 73/279 (26%) in the investigational arm [osimertinib] were assessable. The most common mechanisms of resistance in patients treated with osimertinib were acquired EGFR mutations (21%, especially C797S mutations, all in the cis-position when co-occurring with T790M), MET amplification (19%), cell cycle gene alterations (12%), HER-2 amplification (5%), PI3KCA amplification/mutations (5%), oncogenic fusions (4%) and BRAF V600E (3%). Multiple genetic events co-occurred in 19% of cases. 

Of note, 49% of patients were found to have a loss of T790M, likely to be secondary to the occurrence of competing resistance mechanisms. Of interest, in an explorative analysis of outcomes, loss of T790M was associated with a slightly shorter progression-free survival. Nevertheless, as pointed out by Dr Papadimitrakopoulou, the small number of patients does not allow us to draw definitive conclusions. 

Dr Papadimitrakopoulou closed by stating the analysis confirmed previous findings from smaller studies suggesting acquired EGFR mutations and MET amplification are the most common mechanisms of resistance to osimertinib. She also highlighted the importance of other ongoing studies investigating genetic events leading to resistance to this third generation TKI inhibitor as well as new therapeutic strategies to address them. 

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