T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients
Introduction
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib, has been a big challenge to further improve the prognosis of advanced NSCLC patients [1], [2], [3], [4]. With the analysis of re-biopsies obtained at the time of progression, several resistance mechanisms have been identified including second gatekeeper T790M mutation, MET amplification, small cell histological transformation, HER2 amplification, BRAF mutation, ALK fusion and so on [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Among them, T790M, a secondary mutation in the EGFR gene, has been identified as the major mechanism of acquired EGFR-TKI resistance, accounting for about 50% of TKI resistance [9], [10], [16]. In some studies, T790M mutation showed an indolent nature of the advanced NSCLC with a better prognosis after the discontinuation of EGFR-TKIs [17], [18], [19]; however, in other studies, no association was found between the T790M mutation and overall survival after the therapy of EGFR-TKIs [20], [21]. Meanwhile, clinically, RECIST criteria to define disease progression have been challenged in the EGFR-TKI setting, since progression in EGFR mutated patients after EGFR-TKI treatment seems to be different from what we observe in relapse after chemotherapy. The progression of EGFR-TKI can be divided into three different groups: local progression, gradual progression and dramatic progression [22]. As for the patients with local progression or gradual progression, continuous EGFR-TKIs with or without combination with other treatment modalities showed promising outcomes in several case series [23], [24]. However, until now, there is no biomarker to identify patients who may benefit most from the continuation of TKI treatment.
In this study, we analyzed the prevalence of T790M mutation as an acquired resistance mechanism to EGFR-TKI in a Chinese population with advanced NSCLC and activating EGFR mutation (without T790M at primary diagnosis). We also evaluated the association of secondary T790M mutation with the efficacy of continuous EGFR-TKI treatment after acquired resistance to EGFR-TKI treatment.
Section snippets
Study population
All patients with pathologically confirmed advanced or recurrent stage IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0–2, acquired resistance to EGFR-TKI (gefitinib, erlotinib or icotinib) therapy, and willing to receive re-biopsy to identify potential molecular resistant mechanisms were included. All patients received erlotinib, gefitinib or icotinib orally at a recommended dose, either at first-line therapy, or after first-line standard chemotherapy. Some patients
Patients characteristics
From March 2011 to March 2013, 369 patients with activating EGFR mutation developed acquired resistance to EGFR-TKI in our institute. Among them, 54 patients who underwent re-biopsy and received further therapy with a modified strategy were included in the study. The median age was 51 years (range, 46–67 years). The proportions of males, never smokers and patients with adenocarcinomas were 53.7%, 87.1% and 88.8%, respectively (Table 1). Among them, 22 patients had a local progression and
Discussion
As far as we know, this is the first study to investigate the association of the presence of secondary T790M mutation in re-biopsy samples and outcomes of TKI treatment beyond progression in patients with advanced NSCLC and acquired resistance to EGFR-TKI. We found that the incidence of T790M mutation was found in 53.7% of post-TKI re-biopsy samples. NSCLC patients with local or slow progression had longer PFS and OS if they had a T790M mutation after the failure of EGFR-TKI and received
Conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
This study was supported in part by grants from the National Science Foundation of China (Nos. 81172108 and 81201707), projects of the Science and Technology Commission of Shanghai Municipality (Nos. 11JC1411300, 12ZR1426000, shdc12012111 and 13411950104) and key project of Shanghai Municipal Commission of Health and Family Planning (No. 2013zyjb0401).
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These authors contribute equally to this article.