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Osimertinib Resistance and EGFR Mutations in NSCLC Treatment

*January 2024*

Note: This article discusses the analysis of circulating tumor DNA (ctDNA) in the context of osimertinib treatment for non-small cell lung cancer (NSCLC), specifically focusing on resistance mechanisms. It highlights the complexity of resistance mechanisms associated with osimertinib treatment in NSCLC and the importance of understanding genetic changes for effective management.

The presence of the T790M mutation during first or second-generation EGFR-TKI treatments is observed in 50-60% of patients. This mutation hinders the drug’s binding to the mutant EGFR protein. Osimertinib, however, can covalently bind to the T790M and cysteine-797 (C797) residue at the protein’s ATP binding site, overcoming resistance mechanisms.

Analysis of circulating tumor (ct) DNA at the time of treatment discontinuation or progression showed that 49% of patients in the AURA3 trial lacked the T790M mutation. Often, the loss of T790M is associated with the development of alternative competitive resistance mechanisms. In patients with T790M mutant NSCLC receiving osimertinib, 63% experienced loss of T790M at progression, commonly linked to histological transdifferentiation, KRAS mutations, or gene fusions. In the same study, those with T790M loss had a shorter treatment duration (6.1 months vs. 15.2 months, p = 0.01). T790M loss has been linked to earlier resistance and poorer survival in other cohorts. The presence of T790M loss and plasma EGFR-activating mutations is associated with the shortest PFS (average 2.6 months, 95% CI 1.3, not reached) in genomic analysis of post-progression samples from patients receiving second-line osimertinib. However, when osimertinib is used first-line, the T790M mutation is usually absent before or after progression, reducing its significance with increased frontline use.

Another genetic change at the C797 residue in the ATP binding region of EGFR’s exon 20 has emerged as a key mechanism of resistance to osimertinib. This often involves a cysteine-to-serine (C797S) substitution, and rarely, a cysteine-to-glycine (C797G) change. Mechanistically, osimertinib overcomes T790M resistance by forming a bond with the C797 residue in the ATP pocket; thus, a mutation at C797 hinders its covalent bond with mutant EGFR. Read more.