The EGFR M766Q mutation represents a novel osimertinib resistance mutation in patients with advanced lung adenocarcinoma, as well as a potential therapeutic target, according to study findings published in the Journal of Thoracic Oncology.
The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is frequently used to treat patients with stage IV lung cancer characterized by both an activating EGFR mutation and the EGFR T790M resistance mutation following disease progression on a first-line EGFR TKI. Increasingly, osimertinib is also being used for the first-line treatment of patients with an activating EGFR mutation. Nevertheless, resistance to osimertinib will develop in nearly all patients, and subsequent treatment options are not well established in this setting.
In this case study, a woman aged 79 years with metastatic lung adenocarcinoma characterized by EGFR L858R in exon 21 and EGFR T790M in exon 20 undergoing third-line treatment with osimertinib presented with progressive disease. Circulating tumor cell-free DNA sequencing performed at the time of disease progression revealed the original EGFR L858R activating mutation, no evidence of the EGFR T790M mutation, and the presence of a new EGFR mutation in exon 20, EGFR M766Q. In addition, mutations in TP53 V203M and EGFR S306L were also observed.
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Although the patient decided to continue treatment with osimertinib and subsequently died, the effect of the EGFR M766Q mutation on sensitivity/resistance to different EGFR TKIs was evaluated preclinically through the introduction of EGFR mutations (ie, EGFR L858R alone or both EGFR L858R and EGFR M766Q) into mouse cell lines models (ie, Ba/F3 and NIH/3T3 cells)
Resistance to osimertinib was more than 10-fold higher in Ba/F3 cells expressing the double EGFR mutation compared with EGFR L858R alone. Interestingly, cells characterized by the double EGFR mutant were also comparatively resistant to erlotinib and afatinib, despite earlier observations that some patients with osimertinib-resistant disease (ie, disease characterized by the EGFR C797S mutation) may respond to these agents.
Conversely, sensitivity to low concentrations of neratinib, an irreversible dual EGFR/HER TKI, was similar in Ba/F3 cells expressing either EGFR L858R alone or EGFR L858R and EGFR M766Q. Furthermore, clinically achievable doses of poziotinib, an investigational, irreversible pan-HER TKI, was similarly effective in inhibiting the growth of BaF3 cells expressing either the EGFR L858R mutation alone or with the EGFR M766Q mutation. Overall results were similar in mouse models using NIH-3T3 cells.
The study authors concluded that “additional analysis of large-scale clinical data can provide insight into how frequently this mutation [EGFR M766Q] is encountered. The work presented here suggests that neratinib and poziotinib should be evaluated in the clinic for this novel mechanism of acquired resistance to osimertinib in EGFR-mutant lung cancer.”
Reference
Castellano GM, Aisner J, Burley SK, et al. A novel acquired exon 20 EGFR M766Q mutation in lung adenocarcinoma mediates osimertinib resistance but is sensitive to neratinib and poziotinib: a brief report [published online June 26, 2019]. J Thorac Oncol. doi: 10.1016/j.jtho.2019.06.015
