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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Wednesday, May 31, 2023
Non–small cell lung cancer (NSCLC) tumors harboring EGFR exon 20 insertions generally do not respond to inhibitors of classic activating mutations. So, agents with an improved selectivity profile versus wild-type EGFR are still needed for patients with this type of lung cancer. Gizem Karsli Uzunbas, PhD, of The Broad Institute, Cambridge, Massachusetts, and colleagues observed that understanding these resistance mechanisms may help to identify second-line treatments, such as BAY 2927088—the first reversible inhibitor targeting EGFR exon 20 insertion mutations in NSCLC—for patients who develop resistance to EGFR inhibition. These findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 433/28).
The study used two different methods of in vitro resistance generation to determine the intrinsic and acquired resistance to BAY 2927088 and other EGFR inhibitors for molecular therapies targeting EGFR-mutant NSCLC. BAY 2927088 is currently in phase I clinical trials. Most patients with advanced EGFR-mutant NSCLC eventually experience disease progression because of acquired resistance to EGFR inhibitors.
The first method used in the study to understand BAY 2927088 and other EGFR inhibitors involved initial incubation with a high concentration of inhibitor. The drug-tolerant persister cells that underwent a transcriptional state transition resembling EMT were isolated. The second method used in the study involved gradual escalation of inhibitor concentrations. The study authors identified NRAS hotspot mutations as a mechanism of resistance to BAY 2927088 and other EGFR inhibitors. Additionally, the study authors were creating a parallel approach, to develop a deep-scanning mutagenesis assay of the EGFR kinase domain to identify mutations that may cause resistance in EGFR-mutant NSCLC.
Disclosure: For full disclosures of the study authors, visit www.abstractsonline.com.
