Candidate mutations underlying acquired resistance to osimertinib mapped
medwireNews: Analyses of the FLAURA and AURA3 trials presented at the ESMO 2018 Congress in Munich, Germany, shed light on the genetic mechanisms of acquired resistance to the third generation EGFR–tyrosine kinase inhibitor (TKI) osimertinib.
In both cases, the investigators performed next-generation sequencing of circulating tumor DNA from paired plasma samples – obtained at baseline and at disease progression or treatment discontinuation – to identify genomic alterations. The presenters of both studies noted that the nature of the analyses precluded the identification of non-genetic mechanisms of resistance, such as small-cell transformation and protein expression changes.
Suresh Ramalingam (Emory University, Atlanta, Georgia, USA) reported the findings from FLAURA, which was a phase III trial comparing first-line osimertinib with gefitinib or erlotinib in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).
Among the 91 osimertinib-treated patients with available samples, the most common mutations observed after progression or discontinuation were MET amplifications, at 15%, and secondary EGFR mutations, at 10%, with the EGFR C797S mutation observed most frequently (7%).
In addition to these, alterations were seen in a diverse range of genes such as HER2, BRAF, KRAS, and PIK3CA, at rates of 1–7%. And cell cycle genes were also implicated in the development of acquired resistance to osimertinib; altogether cell cycle gene amplifications were observed in 10% of cases.
Of note, no patient showed evidence of EGFR T790M-mediated acquired resistance, and there was no suggestion that the new mechanisms of resistance lead to more aggressive disease biology, Ramalingam commented.
And he concluded: “Finally, while these data are very helpful in moving the field forward, we feel that definitive tissue based testing is required to understand the full spectrum of resistance mutations and aberrations for patients treated with osimertinib, and ongoing studies including the ELIOS will address this.”
Interestingly, although the AURA3 trial compared osimertinib with platinum-based chemotherapy in the second-line treatment of locally advanced or metastatic NSCLC, the candidate resistance mechanisms were quite similar.
In this case, secondary EGFR mutations were the most frequent, seen in 21% of the 73 patients in the osimertinib group who had available samples, followed by MET amplifications in around 19%. And once again, the most common secondary EGFR mutation was C797S (14%).
Other genes with acquired alterations included cell cycle genes (12%), HER2 (5%), PIK3CA (5%), and BRAF (3%), as seen in the FLAURA study.
The key difference between the two sets of findings related to the EGFR T790M mutation, which was present in the tumor tissue of all participants of the AURA3 trial. Following progression or treatment discontinuation, around half (49%) of the cohort assessed for acquired resistance lost the T790M mutation in their plasma samples, which is consistent with prior reports, said the presenting author Vassiliki Papadimitrakopoulou, from The University of Texas MD Anderson Cancer Center in Houston, USA.
She highlighted that the analysis identified a number of targetable alterations, “which has clinical implications when determining subsequent treatments,” and added that “[r]esearch is ongoing into the novel mechanisms of resistance to osimertinib and therapeutic strategies to address them.”
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