Elsevier

Lung Cancer

Volume 84, Issue 3, June 2014, Pages 295-300
Lung Cancer

T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients

https://doi.org/10.1016/j.lungcan.2014.03.011Get rights and content

Abstract

Background and purpose

Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patients with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression.

Methods

From March 2011 to March 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed at Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status.

Results

A total of 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. In all, 53.7% (29/54) had T790M mutation after the failure of EGFR-TKIs; PFS1 was not statistically significantly different between patients with T790M mutation and without (13.0 vs. 10.5 months, p = 0.894). In all, 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI, 2.689–4.311). Patients with T790M mutation had significantly longer PFS2 (6.3 vs. 2.6 months, p = 0.002) and overall survival (39.8 vs. 23.2 months, p = 0.044) than those without.

Conclusion

Patients with secondary T790M mutation at the time of progression having gradual or local progression after acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790M mutation.

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).

References (35)

  • A.J. Weickhardt et al.

    Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer

    J Thorac Oncol

    (2012)
  • J.F. Gainor et al.

    Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer

    J Clin Oncol

    (2013)
  • K. Ohashi et al.

    Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

    Proc Natl Acad Sci USA

    (2012)
  • W. Pao et al.

    Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain

    PLoS Med

    (2005)
  • S. Kobayashi et al.

    EGFR mutation and resistance of non-small-cell lung cancer to gefitinib

    N Engl J Med

    (2005)
  • J.A. Engelman et al.

    MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling

    Science

    (2007)
  • J. Bean et al.

    MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib

    Proc Natl Acad Sci USA

    (2007)
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