Osimertinib (AZD9291) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated significant clinical benefits in patients with EGFR sensitizing mutations or T790M mutation. However, approximately 5% to 15% of patients with non-small-cell lung cancer (NSCLC) with EGFR T790M mutation has primary resistance to osimertinib treatment. The underlying mechanism is unknown.
A total of 117 patients with stage IIIb-IV EGFR-T790M NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to osimertinib, including FFPE samples, serum samples and serous effusions. We used targeted NGS to detect genes status of patients.
Among 117 patients treated with osimertinib, 82.91% (97/117) developed acquired resistance, and 7.69% (9/117) had primary resistance. Using the specimens at the baseline, there were 3 (33.33%) patients with MET amplification, 1 (11.11%) patient with BCL2L11 loss (BIM deletion polymorphism), 1 (11.11%) patient with ERBB2 amplification, 1 (11.11%) patient with PTEN mutation, 1 (11.11%) patient with EZH2 mutation, and 2 (22.22%) patients with unknown status.
The mechanisms of primary resistance to EGFR-T790M may be highly heterogeneous. BCL2L11 loss, MET amplification, ERBB2 amplification, PTEN mutations, EZH2 mutations might contribute to molecular mechanisms of primary resistance to osimertinib in EGFR-T790M NSCLC. Further investigations are warranted to overcome these primary resistances.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.