非小细胞肺癌中罕见的表皮生长因子受体外显子 19 插入缺失变异对表皮生长因子受体酪氨酸激酶抑制剂疗效的临床影响。
Clinical impact of uncommon epidermal growth factor receptor exon 19 insertion-deletion variants on epidermal growth factor receptor-tyrosine kinase inhibitor efficacy in non-small-cell lung cancer.
机构信息
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China; Graduate School, University of South China, Hengyang, Hunan, 421001, China.
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China.
出版信息
Eur J Cancer. 2020 Dec;141:199-208. doi: 10.1016/j.ejca.2020.10.005. Epub 2020 Nov 7.
AIM
Our study aimed to evaluate the efficacy and resistance mechanisms of first-line epidermal growth factor receptor (EGFR) inhibitor therapy in patients with advanced non-small-cell lung cancer (NSCLC) harbouring uncommon EGFR exon 19 deletion-insertion (19delins) variants.
METHODS
Targeted sequencing data of 2467 treatment-naive patients with NSCLC from January 2015 to August 2018 were retrospectively screened for EGFR exon 19 deletion (19del) variants. Clinical outcomes of 93 patients with uncommon EGFR 19delins and 93 patients with common EGFR 19del were selected through propensity score matching at a ratio of 1:1.
RESULTS
We identified 10 previously unreported EGFR 19delins variants. L747_P753delinsS, L747_A750delinsP and E746_S752delinsV were the most frequent variants, accounting for 33.1% (42/127), 23.6% (30/127) and 12.6% (16/127) of the cases, respectively. Despite similar baseline characteristics, treatment history and response rates, patients with uncommon 19delins had significantly longer median progression-free survival (mPFS) than those with common 19del (19.0 months vs. 13.0 months; p = 0.0016). At progression from first-line EGFR inhibitor therapy, patients with uncommon 19delins and common 19del had similar rates of developing resistance mechanisms including the acquisition of EGFR T790M (45.8% vs 57.8%), small-cell transformation (3.4% vs 3.6%) and MET amplification (5.1% vs 4.8%). For patients whose tumours acquired T790M and who received second-line osimertinib, the mPFS was significantly shorter for patients with uncommon 19delins (n = 27) than those with common 19del (n = 47, 5.0 months vs. 12.0 months; p < 0.0001).
CONCLUSION
Our results suggest that patients with uncommon EGFR 19delins have improved clinical outcomes with first-generation EGFR inhibitor treatment, but inferior outcomes upon the development of T790M resistance mutations.
目的
本研究旨在评估一线表皮生长因子受体（EGFR）抑制剂治疗携带非典型 EGFR 外显子 19 缺失-插入（19delins）变异的晚期非小细胞肺癌（NSCLC）患者的疗效和耐药机制。
方法
回顾性筛选 2015 年 1 月至 2018 年 8 月 2467 例初治 NSCLC 患者的靶向测序数据，以检测 EGFR 外显子 19 缺失（19del）变异。通过倾向性评分匹配，选择 93 例携带非典型 EGFR 19delins 和 93 例携带常见 EGFR 19del 的患者进行 1:1 匹配。
结果
我们鉴定出 10 种先前未报道的 EGFR 19delins 变异。L747_P753delinsS、L747_A750delinsP 和 E746_S752delinsV 是最常见的变异，分别占 33.1%（42/127）、23.6%（30/127）和 12.6%（16/127）。尽管两组患者的基线特征、治疗史和缓解率相似，但与常见 19del 相比，非典型 19delins 患者的中位无进展生存期（mPFS）显著延长（19.0 个月 vs. 13.0 个月；p=0.0016）。在一线 EGFR 抑制剂治疗进展时，非典型 19delins 和常见 19del 患者出现耐药机制的比例相似，包括获得 EGFR T790M（45.8% vs. 57.8%）、小细胞转化（3.4% vs. 3.6%）和 MET 扩增（5.1% vs. 4.8%）。对于接受二线奥希替尼治疗的 T790M 获得性肿瘤患者，非典型 19delins 患者的 mPFS 明显短于常见 19del 患者（n=27 与 n=47，5.0 个月 vs. 12.0 个月；p<0.0001）。
结论
我们的结果表明，携带非典型 EGFR 19delins 的患者接受第一代 EGFR 抑制剂治疗具有更好的临床疗效，但在出现 T790M 耐药突变时疗效较差。
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