EGFR酪氨酸激酶抑制剂对EGFR外显子19插入的非小细胞肺癌患者的疗效：通过lc - scrumm - asia（多机构基因组筛选登记）进行临床-基因组学和临床前分析

IF 4.5 2区医学 Q1 ONCOLOGY

Lung Cancer Pub Date : 2025-03-05 DOI:10.1016/j.lungcan.2025.108479

Yuji Uehara , Hiroki Izumi , Ikei S. Kobayashi , Shingo Matsumoto , Yukio Hosomi , Takae Okuno , Jun Sugisaka , Naoto Takase , Kageaki Taima , Shinichi Sasaki , Shuhei Teranishi , Shingo Miyamoto , Masahide Mori , Chiho Nakashima , Shuichi Asano , Hajime Oi , Tetsuya Sakai , Yuji Shibata , Hibiki Udagawa , Eri Sugiyama , Koichi Goto

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引用次数: 0

摘要

EGFR外显子19插入（EGFRex19ins）是罕见的EGFR突变。他们的临床基因组特征和使用egfr -酪氨酸激酶抑制剂（TKIs）的结果仍不确定。方法：我们在多机构前瞻性肺癌基因组筛查项目（lc - scruma - asia）中评估EGFR-TKIs检测egfrex19蛋白的临床基因组特征和结果。我们还研究了表达EGFR- k745_e746insipvaik （Ba/F3- ipvaik）的临床前Ba/F3模型，以研究它们对第一代、第二代、第三代和EGFR外显子20插入活性TKIs的敏感性。结果LC-SCRUM-Asia在2015年3月至2023年12月期间纳入了16,204例NSCLC患者。在13份样本中检测到EGFRex19ins（占NSCLC的0.1%）。中位年龄为72岁（38-80岁）；大多数患者为女性（77%），患有腺癌（92%），从不吸烟（62%）。12名患者（93%）有EGFR-K745_E746insIPVAIK，而1名患者（7%）有EGFR-K745_E746insVPVAIK。最常见的共突变是TP53 (62%)；没有患者有其他的驱动改变。6名患者（46%）在基于pcr的Cobas EGFR检测中检测出EGFR外显子19缺失阳性，可能是由于序列同源性引起的交叉反应性。12例患者接受EGFR-TKIs治疗；5例（42%）出现部分缓解。在临床前研究中，与其他EGFR-TKIs相比，Ba/F3-IPVAIK对第二代EGFR-TKIs的敏感性最高。结构研究支持这些一致的结果。当按EGFR-TKI世代细分时，第一代、第二代和第三代tki的缓解率分别为50%（1/2）、80%（4/5）和0%（0/5）。第一代、第二代和第三代tki的中位PFS分别为8.7个月（95% CI, 7.4 nr）、14.7个月（95% CI, 8.0 nr）和4.4个月（95% CI, 3.4 nr）。我们的临床前、结构和临床研究结果表明，与其他TKIs相比，第二代EGFR-TKIs对EGFRex19ins更有效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Efficacy of EGFR tyrosine kinase inhibitors in patients with non–small cell lung cancer with EGFR exon 19 insertions: clinical-genomic, preclinical analysis through LC-SCRUM-Asia (multi-institutional genomic screening registry)

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Background

EGFR exon 19 insertions (EGFRex19ins) are rare EGFR mutations. Their clinical-genomic characteristics and outcomes with EGFR-tyrosine kinase inhibitors (TKIs) remain uncertain.

Methods

We evaluated the clinical-genomic characteristics and outcomes of EGFR-TKIs for EGFRex19ins in the multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia). We also studied preclinical Ba/F3 models expressing EGFR-K745_E746insIPVAIK (Ba/F3-IPVAIK) to investigate their sensitivity to 1st-, 2nd-, 3rd-generation, and EGFR exon 20 insertion-active TKIs.

Results

In LC-SCRUM-Asia, 16,204 NSCLC patients were enrolled from March 2015 to December 2023. EGFRex19ins were detected in 13 samples (0.1 % of NSCLC). The median age was 72 years (range, 38–80); most patients were female (77 %), had adenocarcinoma (92 %), and were never-smokers (62 %). Twelve patients (93 %) had EGFR-K745_E746insIPVAIK, while one (7 %) had EGFR-K745_E746insVPVAIK. The most frequent co-mutation was TP53 (62 %); no patients had other driver alterations. Six patients (46 %) tested positive for EGFR exon 19 deletions with PCR-based Cobas EGFR test, likely due to cross-reactivity arising from sequence homology. Twelve patients received EGFR-TKIs; five (42 %) experienced partial response. In the preclinical study, Ba/F3-IPVAIK showed the highest sensitivity to 2nd-generation EGFR-TKIs compared to other EGFR-TKIs. Structural studies supported these consistent results. When broken down by EGFR-TKI generations, response rates for 1st-, 2nd-, and 3rd-generation TKIs were 50 % (1/2), 80 % (4/5), and 0 % (0/5), respectively. The median PFS for 1st-, 2nd-, and 3rd-generation TKIs were 8.7 (95 % CI, 7.4–NR), 14.7 (95 % CI, 8.0–NR), and 4.4 (95 % CI, 3.4–NR) months, respectively.

Conclusion

Our preclinical, structural, and clinical findings indicate 2nd-generation EGFR-TKIs are more effective for EGFRex19ins compared to other TKIs.

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来源期刊

Lung Cancer 医学-呼吸系统

CiteScore

9.40

自引率

3.80%

发文量

407

审稿时长

25 days

期刊介绍： Lung Cancer is an international publication covering the clinical, translational and basic science of malignancies of the lung and chest region.Original research articles, early reports, review articles, editorials and correspondence covering the prevention, epidemiology and etiology, basic biology, pathology, clinical assessment, surgery, chemotherapy, radiotherapy, combined treatment modalities, other treatment modalities and outcomes of lung cancer are welcome.