Targeted sequencing of patients with acquired resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) for EGFR T790M-mutant non-small cell lung cancer (NSCLC) revealed that resistance is associated with diverse pathways.

The retrospective study looked at the genomic landscape of 113 specimens taken from patients with EGFR-mutant disease who had been previously treated with olmutinib or osimertinib. Patients had rebiopsy of the disease before treatment (77 patients) or after progression (36 patients). Of the 98 samples included, 54% were treated with osimertinib and 46% with olmutinib.

Looking only at posttreatment biopsies, the study showed that a little less than one-third of patients had EGFR-dependent mechanisms detected in their tumor samples. These included C797S, occurring in 25% of posttreatment samples, and L718Q mutations.

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More than half of patients had EGFR-independent mechanisms detected.

“The EGFR-independent resistance mechanisms reported in previous studies include small cell transformation; PIK3CA, PTEN, and BRAF mutation; FGFR1, MET, and HGF amplification; and CDKN2A deletion,” the researchers wrote. “In our study cohort, the incidences of the aforementioned EGFR-independent pathways were 65% (11/17) in patients treated with osimertinib and 53% (10/19) in those treated with olmutinib.”

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Approximately 40% of patients had a disappearance of EGFR T790M. Of these, 59% had been treated with osimertinib and 21% with olmutinib. According to the researchers, those patients who lots the T790M mutation were more likely to show EGFR-independent pathways as a secondary resistance mechanism.

“These results suggest that there is a difference in the nature of resistance acquired after treatment with third-generation EGFR-TKIs, although not statistically significant according to the specific drug used,” the researchers wrote.


Lee J, Kim HS, Lee B, et al. Genomic landscape of acquired resistance to third-generation EGFR tyrosine kinase inhibitors in EGFR T790M-mutant non-small cell lung cancer[published online March 10, 2020]. Cancer. doi: 10.1002/cncr.32809