An Observational Study of Acquired EGFR T790M-Dependent Resistance to EGFR-TKI Treatment in Lung Adenocarcinoma Patients in Taiwan

Abstract

In Taiwan, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib are served as first-line therapy for non-small lung cell cancer (NSCLC) patients with EGFR sensitizing mutations. However, the majority of patients who initially respond to EGFR-TKIs, progress through acquiring EGFR T790M mutations (T790M), which is the most common resistant mechanism. Patients with T790M gain the opportunity of subsequent treatment with third-generation EGFR-TKI, osimertinib. This study aimed to evaluate the association between prior EGFR-TKI therapy and incidence of acquired T790M resistance in lung adenocarcinoma patients who have progressed on first/second-generation EGFR-TKI therapy. This retrospective study included lung adenocarcinoma patients who had a radiographically-confirmed progressive disease under EGFR-TKI treatment and had re-biopsy samples for T790M testing from seven medical centers in Taiwan from June 2013 to December 2018. Patients harboring de novo T790M or using more than one EGFR-TKI were excluded. Of the 407 patients enrolled, the overall T790M acquisition rate was 52.8%. The patients treated with gefitinib, erlotinib or afatinib had a statistically significant difference in the T790M rates (59.9, 45.5, and 52.7%, respectively; p = 0.037) after disease progression. Patients with common baseline EGFR mutations (Del-19 and L858R) (p = 0.005) and longer treatment duration with EGFR-TKIs (p < 0.001) had higher chances of T790M acquisition. Multivariate logistic regression analysis further showed that patients with common baseline EGFR mutations, gefitinib (compared to erlotinib) administration, and longer treatment duration with EGFR-TKIs had higher T790M incidence. There was no significant difference in the incidence of acquired T790M between different re-biopsy tissue samples or complications. In conclusion, this study showed that patients who progressed from gefitinib treatment, bearing common EGFR mutations, and with longer EGFR-TKI treatment duration had increased incidence of T790M acquisition and, therefore, were suitable for subsequent osimertinib treatment.

Keywords: afatinib; epidermal growth factor receptor mutation; erlotinib; gefitinib; non-small cell lung cancer; osimertinib; tyrosine kinase inhibitor.

Figure 1

The flow chart of patient enrollment. *There were 12 patients who switched to another EGFR-TKI as a first-line treatment due to the side effects (see Supplementary Figure 1).

Figure 2

The different EGFR mutation types among the three areas in Taiwan. (p = 0.384).

Figure 3

The comparison of acquired T790M incidence between the three different EGFR-TKIs (Gefitinib vs. Erlotinib vs. Afatinib: 59.9 vs. 45.5 vs. 52.7%; respectively, p = 0.037).

Figure 4

Kaplan-Meier survival curves of time to treatment discontinuation (TTD) in the three EGFR-TKI-treated adenocarcinoma patient cohorts. There was a significant difference between gefitinib (n = 162), erlotinib (n = 154), and afatinib (n = 91) (gefitinib vs. erlotinib vs. afatinib: 16.2 months vs. 12.1 months vs. 14.4 months, respectively; p = 0.001).

Figure 5

The comparison of acquired T790M incidence between different times to treatment discontinuation (TTD) of EGFR-TKIs (p < 0.001 by Chi-square test).

Figure 6

The comparison of acquired T790M incidence between the different baseline EGFR mutation types (Del-19 vs. L858R vs. Other: 58.2 vs. 50.3 vs. 22.7%; p = 0.004). Del-19, deletion in exon 19; ns, not significant.