Purpose: Third-generation epidermal growth factor receptor () tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes.
Methods: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs.
Results: Co-occurring genetic aberrations were found in 74.4% of p.T790-positive samples (n = 124). Mutations in were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor () amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 8.2 months; 95% CI, 1.69 to 14.77 months; ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, amplification, mutations).
Conclusion: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446436 | PMC |
| http://dx.doi.org/10.1200/PO.18.00210 | DOI Listing |
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