表皮生长因子受体突变型晚期非小细胞肺癌免疫治疗的研究进展

Advances in immunotherapy of advanced non-small cell lung cancer with EGFR mutation

亚洲人群非小细胞肺癌(non-small cell lung cancer,NSCLC)表皮生长因子受体(epidermal growth factor receptor,EGFR)突变发生率显著高于西方人群。近年来,以针对程序性死亡因子1(programmed cell death 1,PD-1)及程序性死亡因子配体1(programmed cell death ligand 1,PD-L1)抗体药物为代表的免疫治疗已成为晚期NSCLC临床治疗方案之一,开启肺癌免疫治疗新时代;然而既往研究报道EGFR突变型晚期NSCLC患者未能从免疫治疗单药中获益,不同EGFR突变型的患者对免疫治疗的响应也存在差异。最新临床研究ORIENT-31中期分析结果显示,免疫治疗联合化疗和抗血管生成药物显著改善了EGFR酪氨酸激酶抑制剂耐药的晚期NSCLC患者的无进展生存期,为此类EGFR突变型患者提供了新的临床治疗策略。EGFR突变型肿瘤组织微环境呈免疫抑制的状态,通过靶向肿瘤免疫抑制中发挥重要作用的靶点,促进EGFR突变型肿瘤对免疫治疗的响应,获得增效的新免疫联合治疗策略,可以丰富EGFR突变型晚期NSCLC患者在靶向治疗耐药后的临床治疗选择,进一步改善此类患者的生存预后。该文就EGFR突变型晚期NSCLC免疫治疗的最新临床研究进展、不同EGFR突变型免疫治疗效果差异、EGFR突变型NSCLC免疫联合治疗的增敏机制和潜在联合治疗方案进行综述。

The incidence of epidermal growth factor receptor(EGFR)mutation in non-small cell lung cancer(NSCLC)in Asians is significantly higher than that in Westerners.For the past few years,immune checkpoint inhibitors(ICIs)that target the programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)axis have become a part of the treatment paradigm for advanced NSCLC,opening a new era of immunotherapy for lung cancer.However,previous clinical trials reported that advanced NSCLC patients with EGFR mutation could not benefit from ICIs monotherapy.The immunotherapy outcomes of different EGFR mutant subtypes showed diverse.The interim results of the latest clinical trial ORIENT-31 showed that immunotherapy combined with chemotherapy and anti-angiogenesis significantly improved the progression-free survival of EGFR tyrosine kinase inhibitors(TKIs)resistant advanced NSCLC patients,providing a new therapeutic strategy for those EGFR mutant patients.The tumor microenvironment of EGFR-mutated NSCLC is immunosuppressed.Targeting the key immunomodulatory factors that play important roles in the immunosuppression may promote the response of EGFR-mutated tumors to immunotherapy and provide a new synergistic immune combination therapy strategy,which will enrich the clinical treatment options and improve the survival prognosis of EGFR-TKIs-resistant NSCLC patients.This article summarizes the latest clinical progression of immunotherapy in advanced NSCLC with EGFR mutation,the differences of immunotherapy efficacy among different EGFR mutation subtypes,the synergistic mechanism of combined immunotherapy and the potential molecular target combining with immunotherapy in EGFRmutated NSCLC.