EGFR靶向治疗的现状 机遇和挑战

Current status,opportunities and challenges of EGFR-targeted therapy

肺癌是癌症相关死亡的主要原因。目前,肺癌的发病率正在下降,但患者的生存率仍然较低。肺癌中超过85%是非小细胞肺癌(non-small cell lung cancer, NSCLC),超过60%的NSCLC表达表皮生长因子受体(epidermal growth factor receptor,EGFR),该类突变在肺腺癌、女性、亚洲人群和从未吸烟的人群中更常见。EGFR已成为NSCLC的重要治疗靶点,目前已开发出多种靶向药物,包括小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)和单克隆抗体。EGFR-TKIs现已开发至第四代,并改写了EGFR突变型NSCLC的诊疗指南。在所有EGFR突变中,18号外显子(G719A/C)、21号外显子(L858R和L861Q)的点突变以及19号外显子框内缺失突变(Exon19 del)对TKIs高度敏感,其中Exon19 del敏感性最高。尽管EGFR靶向治疗效果显著,但几乎所有患者最终均会产生耐药。最常见的耐药突变是T790M突变,其他耐药突变包括D761Y、T854A和L747S等。本文对近几年EGFR靶向治疗的进展进行综述。

Lung cancer is the leading cause of cancer-related deaths.Although the current incidence of lung cancer is decreasing,the survival rate of patients remains very low.Non-small cell lung cancer(NSCLC)accounts for more than 85%of lung cancer cases.Furthermore,in more than 60%of cases,NSCLC expresses the epidermal growth factor receptor(EGFR).Such mutations are more common in people with lung adenocarcinoma,women,Asians,and people who have never smoked.EGFR has become an important therapeutic target for NSCLC,and several targeted drugs,including small-molecule tyrosine kinase inhibitors(TKIs)and monoclonal antibodies,have been developed.Fourth-generation EGFR-TKIs have also been developed,and the guidelines for diagnosing and treating patients with EGFR-positive NSCLC have been revised.Among all EGFR mutations,point mutations in exon 18(G719A/C)and exon 21(L858R and L861Q)and in-frame deletion mutations in exon 19(Exon19 del)are highly sensitive to TKIs.Exon19 del is the most sensitive of all mutations.Although EGFR-targeted therapy is very effective for advanced NSCLC,almost all patients eventually develop drug-resistant mutations.The most common drug-resistant mutation is the T790M mutation,and other mutations include D761Y,T854A,and L747S.This study reviews the progress of EGFR-targeted therapy in recent years,particularly in the past year.