在 EGFR 突变型 NSCLC 中先前的 EGFR-TKI 治疗会影响获得性 T790M 的等位基因频率分数和奥希替尼的后续疗效。
Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib.
机构信息
Divison of Lung Cancer and Interventional Bronchoscopy, Department of Thoracic Medicine, College of Medicine, Chang Gung Memorial Hospital, Chang Gung University, No. 199, Tun-Hwa North Road, Taipei, Taiwan.
Department of Computing, Imperial College London, Data Science Institute, London, UK.
出版信息
Target Oncol. 2019 Aug;14(4):433-440. doi: 10.1007/s11523-019-00657-1.
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 (AF) to EGFR-activating mutations (AF) 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). AF and AF 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 AF to AF 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 AF to AF correlates with the efficacy of osimertinib. We found all patients in ARC2 having the highest ratio of AF to AF 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.
背景
第一代（1G）和第二代（2G）表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）对 EGFR T790M 突变的非小细胞肺癌（NSCLC）细胞具有不同的抑制能力。
目的
评估接受 1G 和 2G EGFR TKI 治疗后获得 T790M 介导耐药的患者中 T790M（AF）与 EGFR 激活突变（AF）等位基因分数的比值，并确定 AF 与奥希替尼后期疗效的关系。
患者和方法
根据先前使用 EGFR TKI 的代际（1G 与 2G），对 54 例 T790M 阳性 EGFR 突变 NSCLC 患者的奥希替尼疗效进行了回顾性分析。通过在获得性耐药时获得的组织，使用 QuantStudio 数字 PCR 来确定 AF 和 AF。
结果
与 2G 组相比，1G 组的无进展生存期（PFS；20.3 个月比 11.6 个月，p=0.031）和 1 年 PFS 率（63.2%比 37.5%，p=0.029）显著更好。1G 组的 AF 与 AF 的比值明显高于 2G 组（46.16±5.40%比 25.86±4.25%，p=0.009）。一项无偏分析显示了三个 AF 相关聚类（ARC），表明 AF 与 AF 的比值与奥希替尼的疗效相关。我们发现，所有在 ARC2 中具有最高 AF 与 AF 比值的患者先前均接受过 1G EGFR TKI 治疗，与 ARC3（NR 比 11.9 个月，p=0.060）和 ARC1（NR 比 12.4 个月，p=0.045）相比，奥希替尼 PFS 最长。
结论
获得性 EGFR 突变 NSCLC 的 T790M 分数与先前 EGFR TKI 代际的使用和奥希替尼的后期疗效相关。
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