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Targeted Oncology
Published in: Targeted Oncology 4/2019

01-08-2019 | NSCLC | Original Research Article

Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib

Authors: Chih-Hsi Scott Kuo, Chi-Hsien Huang, Chien-Ying Liu, Stelios Pavlidis, Ho-Wen Ko, Fu-Tsai Chung, Tin-Yu Lin, Chih-Liang Wang, Yi-Ke Guo, Cheng-Ta Yang

Published in: Targeted Oncology | Issue 4/2019

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Abstract

Background

The first (1G) and second (2G) generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show differential inhibitory capacities towards EGFR T790M-mutated non-small-cell lung cancer (NSCLC) cells.

Objective

To assess the ratio of the allele fractions of T790M (AFT790M) to EGFR-activating mutations (AFmEGFR) in patients treated with 1G and 2G EGFR TKIs who acquired T790M-mediated resistance and to determine the relationship between AF and the later efficacy of osimertinib.

Patients and methods

The efficacy of osimertinib was reviewed for 54 T790M-positive EGFR-mutated NSCLC patients grouped by the generation of prior EGFR TKI use (1G vs. 2G). AFmEGFR and AFT790M were determined by QuantStudio digital PCR using tissues obtained upon acquired resistance.

Results

The progression-free survival (PFS; 20.3 vs. 11.6 months, p = 0.031) and the 1-year PFS rate (63.2 vs. 37.5%, p = 0.029) for osimertinib were significantly better for group 1G compared to group 2G. The ratio of AFT790M to AFmEGFR in group 1G was significantly higher than in group 2G (46.16 ± 5.40% vs. 25.86 ± 4.25%, p = 0.009). An unbiased analysis revealed three AF-associated clusters (ARCs) suggesting the ratio of AFT790M to AFmEGFR correlates with the efficacy of osimertinib. We found all patients in ARC2 having the highest ratio of AFT790M to AFmEGFR to have previously been treated with a 1G EGFR TKI and to show the longest osimertinib PFS compared to ARC3 (NR vs. 11.9 months, p = 0.060) and ARC1 (NR vs. 12.4 month, p = 0.045).

Conclusions

Acquired T790M fraction of EGFR-mutated NSCLC is linked to different generations of prior EGFR TKI use and the later efficacy of osimertinib.
Appendix
Available only for authorised users
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Metadata
Title
Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib
Authors
Chih-Hsi Scott Kuo
Chi-Hsien Huang
Chien-Ying Liu
Stelios Pavlidis
Ho-Wen Ko
Fu-Tsai Chung
Tin-Yu Lin
Chih-Liang Wang
Yi-Ke Guo
Cheng-Ta Yang
Publication date
01-08-2019
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 4/2019
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-019-00657-1

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