Optimizing diagnosis and treatment of EGFR exon 20 insertions mutant NSCLC

The Epidermal growth factor receptor (EGFR) exon (ex) 20 insertions (ins) has been considered as an "undruggable target" for a long time, with platinum-pemetrexed combination recommended as upfront standard treatment for newly diagnosed advanced non-small cell lung cancer (NSCLC) patients. Recent preliminary data from early phase clinical trials have demonstrated that pharmacological inhibition of EGFRex20ins is possible, offering new treatment opportunities to 1-2% of advanced NSCLC patients harboring such hard-to-treat molecular alteration. Among the different drugs under clinical investigation, both amivantamab and mobocertinib have received regulatory approval in the United States, by the Food and Drugs Administration (FDA), while amivantamab has been recently approved also in Europe, for the clinical treatment of advanced NSCLC patients harboring EGFRex20ins who failed at least one prior line of systemic therapy, representing a major breakthrough in lung cancer treatment over the last year. With novel effective targeted options on the horizon, there is a renewed interest on optimizing the molecular screening of advanced NSCLC, and next-generation sequencing (NGS)-based genotyping is currently considered the gold standard approach to profile advanced NSCLC patients, as recom-mended by international guidelines. Herein we provide an updated overview of the most recent findings and upcoming challenges regarding both molecular detection and therapeutic management of EGFR ex20ins mutant advanced NSCLC patients.