Nat Commun: The clinical impact of EGFR T790M mutation in advanced non-small cell lung cancer

The identification of genomic drivers of non-small cell lung cancer ( NSCLC ) is the key to the development of targeted therapies, such as TKIs (tyrosine kinase inhibitors) that activate EGFR (epidermal growth factor receptor) gene mutants.
However, cancer cells usually protect themselves from such personalized therapies in a variety of ways.

This kind of cancer evolution caused by treatment will lead to the subcloning of genomic diversity within a single tumor and lead to the emergence of treatment resistance.
Previous studies have shown that EGFR T790M secondary mutation is the most common type of drug resistance mutation in EGFR-mutant NSCLC patients treated with first-generation or second-generation TKIs.
At present, the standard of treatment for such patients is to use the third-generation EGFR-TKI osimertinib , which can irreversibly inhibit EGFR activation (L858R, exon 19 deletion) and drug resistance (T790M) mutations The activity of wild-type EGFR is weak.

In this study, the researchers revealed that the size of EGFR T790M mutation-positive clones affects its response to osimertinib.
Through retrospective NGS analysis of baseline plasma ctDNA samples of 289 advanced NSCLC patients with T790M mutation in the AURA3 phase III trial, the researchers evaluated the shorter progression-free treatment of T790M subclones and osimertinib in the treatment and chemotherapy regimens.
Relevance of life span (PFS).

The T790M subclone is associated with the tumor response of osimertinib and chemotherapy and the patient's PFS

Both baseline ctDNA and longitudinal ctDNA analysis showed that the T790M subclonal tumor was enriched with PIK3CA, which indicated that the resistance of osimertinib conferred in vitro could be partially reversed by PI3K signaling pathway inhibitors.

All in all, the results of this study clarify the impact of tumor heterogeneity on the response of advanced NSCLC patients to osimertinib, which may help determine the combined treatment strategy for these patients.