Investigation of the mechanisms of resistance to osimertinib in patients with T790M-associated NSCLC

Stepanova, M.; Моисеенко, Ф. В.; Жабина, А. С.; Клименко, В. В.; Rysev, N.; Myslik, A.; Artemieva, E. V.; Shelekhova, Ksenya V.; Богданов, А. А.; Volkov, Nikita; Моисеенко, В.

doi:10.1093/annonc/mdz413.058

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“…The incidence of C797X mutations is 15% at disease progression on second-line osimertinib in the AURA3 trial, whereas they were detected in only 7% of patients in the firstline setting of the FLAURA trial at the time of disease progression [57,58]. In other studies, the prevalence of C797X mutations ranges from 0 to 29%, at least in part reflecting intratumor heterogeneity [56,[60][61][62][63][64][65][66].…”

Section: C797smentioning

confidence: 96%

“…Mutations at other amino acid residues of EGFR have also been confirmed to confer resistance to osimertinib. G796 is located under the phenyl aromatic ring of osimertinib, where solvent-front resistant mutations occur and G796X mutations (G796D, G796R and G796S) sterically hamper the binding of osimertinib to the EGFR intracellular kinase domain [60,[66][67][68]. Similarly, L792 has a close interaction with the methoxy group on the aromatic ring of osimertinib, generating steric hindrance to osimertinib [56,66].…”

Section: Other Egfr-dependent Resistance Mechanismsmentioning

confidence: 99%

“…Histologic transformation from NSCLC to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC) has been identified in 2-15% of patients subjected to progression on osimertinib treatment [60,63,94]. Complete inactivation of both RB1 and TP53 was strikingly associated with an increased risk of transformation from NSCLC to SCLC among EGFR-mutant lung adenocarcinomas, suggesting the predictive value of these two mutations in SCLC transformation [95,96].…”

Section: Histologic Transformationsmentioning

confidence: 99%

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Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance

et al. 2022

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.

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