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

Shang-Gin Wu,Chien-Ying Liu,Te-Chun Hsia,Chi-Lu Chiang,Chi-Lu Chiang,Chi-Lu Chiang,Chi-Lu Chiang,Jin-Yuan Shih,Po-Lan Su,Chin-Chou Wang,Chin-Chou Wang,Gee-Chen Chang,Gee-Chen Chang,Gee-Chen Chang

doi:10.3389/fonc.2020.01481

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.

Highlights

Lung cancer is the most commonly diagnosed cancer and the leading cause of all cancer-related mortalities in Taiwan and worldwide [1, 2]
There was no significant difference in different EGFR mutation rates, including Del-19, L858R, or uncommon EGFR mutation, among the three areas in Taiwan (p = 0.384) (Figure 2)
A higher incidence was observed in patients treated with gefitinib than in those treated with erlotinib (p = 0.010)

Summary

Introduction

Lung cancer is the most commonly diagnosed cancer and the leading cause of all cancer-related mortalities in Taiwan and worldwide [1, 2]. Most of the lung cancers are diagnosed at advanced or metastatic stages with lower 5-year survival rates [1]. In Taiwan, 54.1% of all the newly diagnosed lung cancer cases are at stage IV, with a median survival time of 9 months [2]. 85% of primary lung cancers are classified as non-small-cell lung cancer (NSCLC), with adenocarcinoma being the most common subtype. Somatic mutations in the EGFR gene are frequently found in adenocarcinomas [3, 4]. The exon 19 deletion (Del-19) and exon 21 L858R (L858R) together account for 90% of the EGFR mutations. Other clinically relevant mutations include G719X, L861X, exon 20 insertions, etcetera [5]

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