Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma.
Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma.
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DOI：
10.1158/2159-8290.cd-17-1260
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发表时间：
2018-06
期刊：
影响因子：
28.2
通讯作者：
Catenacci DVT
中科院分区：
文献类型：
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作者：
Maron SB;Alpert L;Kwak HA;Lomnicki S;Chase L;Xu D;O'Day E;Nagy RJ;Lanman RB;Cecchi F;Hembrough T;Schrock A;Hart J;Xiao SY;Setia N;Catenacci DVT
以前在未选择的胃食管腺癌(GEA)患者中进行的抗EGFR试验都是响亮的阴性。在芝加哥大学，我们在5%(19/363)的患者中发现了EGFR扩增，其中包括6%(8/140)的患者，他们接受了前瞻性筛查，并打算使用抗EGFR治疗进行治疗。7例患者接受≥1剂治疗：3例一线联用ABT806，1例二线联用西妥昔单抗，3例单用三、四联西妥昔单抗。治疗有效率为58%(4/7)，疾病控制率为100%(7/7)，中位无进展生存期为10个月。治疗前后的肿瘤NGS、连续血浆ctDNA NGS和肿瘤IHC/FISH检测EGFR发现了预先存在和/或获得性的基因组事件，包括EGFR阴性克隆、PTEN缺失、KRAS扩增/突变、NRAS、MYC和HER2扩增，以及作为耐药机制的GNAS突变。两名可评估的患者CD3+浸润率间期增加，包括一名NKp46+和PD-L1 IHC表达较基线增加，提示免疫治疗的作用机制。EGFR扩增预测了抗EGFR治疗的益处，尽管直到出现了各种耐药机制。
Previous anti-EGFR trials in unselected gastroesophageal adenocarcinoma (GEA) patients were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven pts received ≥1 dose of treatment: three first line FOLFOX plus ABT-806, one second line FOLFIRI plus cetuximab, and three third/fourth line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pre and post-treatment tumor NGS, serial plasma ctDNA NGS, and tumor IHC/FISH for EGFR revealed pre-existing and/or acquired genomic events including EGFR negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.