...Patients with stage Ia-IIa non-small cell lung cancer who received complete surgical radical resection with negative margins (R0) and complete lymph node dissection with EGFR mutations (except those reported in the literature that are associated with osimertinib resistance); EGFR mutations, such as L718Q, C797S, etc.); 4. ...

Between January 1, 2016 and October 31, 2020, a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy at Daping Hospital (Chongqing, China) were retrospective screened....A total of 21 patients underwent repeated NGS tests upon osimertinib resistance. MET amplification was the most common resistance mechanism (6/21, 28.6%), followed by C797S mutation (5/21, 23.8%).

...40 patients were proven to have EGFR T790 M by tumour biopsy in 16 patients and liquid biopsy in 24 patients after acquiring drug resistance to the first generation of EGFR-TKIs. All of these patients received osimertinib as second-line therapy and reached a PFS of 3–39 months for osimertinib. Ten patients underwent rebiopsy, including lung and lymph node biopsy, to analyse resistance-related mutations, including C797S and MET, by NGS panel....EGFR C797S mutation and MET amplification are leading mechanisms for osimertinib resistance in lung cancer.

Table 2 Molecular alterations detected in ctDNA upon progression to osimertinib treatment

The paired baseline and progression sample analysis identified the emergence of acquired mutations, EGFR C797S (n = 1), KRAS G12D (n = 1), and PIK3CA E545K mutations (n = 2), in the progression samples. One of these progression tissue samples with an acquired PIK3CA mutation also lost EGFR....Our multi-layered molecular analysis of osimertinib-resistant patients’ clinical samples and patient-derived cancer models demonstrates a diverse spectrum of osimertinib resistance...

...epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers…The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation...

Cells expressing the C797S-mutant construct were markedly less sensitive to AZD9291 in terms of cell growth and EGFR phosphorylation (Figs. 1b–c, Supplementary Fig. 2); they were similarly resistant to CO-1686, a second mutant-selective EGFR TKI which has induced responses in T790M+ lung cancer12. We therefore hypothesized that EGFR C797S could be a common mediator of acquired resistance to AZD9291 in patients.