EGFR突变的晚期非小细胞肺癌患者接受一代TKI靶向治疗的效果及预后预测因子分析

Efficacy and prognostic predictors of first-generation EGFR TKI-targeted therapy in patients with EGFRmutated advanced non-small cell lung cancer

背景和目的:表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)治疗已成为EGFR突变的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的一线标准治疗,然而仍有10%~30%的EGFR敏感突变的NSCLC患者在接受TKI靶向治疗时出现原发性耐药。因此,研究EGFR-TKI的临床疗效,寻找其预后预测因子对于治疗携带EGFR敏感突变的晚期NSCLC患者具有重要的指导意义。本研究旨在探讨埃克替尼一线治疗EGFR突变的晚期NCSLC患者的疗效并寻找其预后预测因子。方法:筛选2016年1月—2017年11月福建省肿瘤医院收治的携带EGFR突变的258例ⅢB~Ⅳ期NSCLC患者,并采外周血检测循环肿瘤DNA(circulating tumor DNA,ctDNA)中的EGFR突变情况,最终入组118例,均接受埃克替尼125 mg口服,每天3次。定期收集患者的生存资料。应用χ^(2)检验比较不同EGFR突变组的临床病理学特征的差异。采用Kaplan-Meier生存曲线分析患者的无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS),应用log-rank检验进行单因素分析,应用COX回归模型进行多因素分析。结果:118例患者的客观缓解率(objective response rate,ORR)为62.7%(95%CI:53.9%~71.6%),疾病控制率(disease control rate,DCR)为92.4%(95%CI:87.5%~97.2%),中位PFS为11.3个月(95%CI:9.1~13.5个月),中位OS为32.0个月(95%CI:26.9~37.1个月)。不同EGFR表达类型之间的临床病理学特征差异无统计学意义(P>0.05),但不同EGFR突变组患者的最佳疗效差异有统计学意义(P=0.040)。单因素分析显示,外周血ctDNA的EGFR突变情况与患者的PFS和OS无关(P>0.05)。多因素分析显示,基线乳酸脱氢酶(lactate dehydrogenase,LDH)表达水平、EGFR类型、胸腔积液及最佳疗效为PFS的独立预测因子。而患者的N分期、骨转移、PFS及出现EGFR T790M突变是OS的独立预测因子。结论:EGFR突变的晚期NSCLC患者接受一线埃克替尼靶向治疗具有良好的疗效。外周血ctDNA中的EGFR突变情况与患者的临床疗效无关。骨转移与接受TKI靶向治疗患者的不良预后有关。

Background and purpose:Epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI)treatment has become the first-line standard treatment for advanced non-small cell lung cancer(NSCLC)with EGFR mutation.However,10%-30%of NSCLC patients with EGFR sensitive mutation still have primary drug resistance when receiving TKI targeted therapy.Therefore,to study the clinical efficacy of EGFR-TKI and find out its prognostic predictors has important significance for the treatment of advanced NSCLC patients with EGFR sensitive mutation.The purpose of this research was to evaluate the efficacy of icotinib as first-line treatment in patients with EGFR-mutant advanced NSCLC and investigate the prognostic predictors.Methods:A total of 258 stageⅢB-ⅣNSCLC patients with EGFR mutation who were admitted to Fujian Cancer Hospital from January 2016 to November 2017 were selected.One hundred and eighteen advanced NSCLC patients with EGFR mutation were enrolled,and baseline circulating tumor DNA(ctDNA)EGFR-mutant status was determined using the plasma test.All these patients received icotinib 125mg three times a day.Theχ^(2) test was used to compare the differences in clinicopathological characteristics between different EGFR mutation groups.Progression-free survival(PFS)and overall survival(OS)were estimated by the Kaplan-Meier survival curve.The log-rank test was used for univariate analysis,and the COX regression model was used for multivariate analysis.Results:The objective response rate(ORR)of 118 patients was 62.7%(95%CI:53.9%-71.6%),the disease control rate(DCR)was 92.4%(95%CI:87.5%-97.2%),and the median PFS was 11.3months(95%CI:9.1-13.5 months),and the median OS was 32.0 months(95%CI:26.9-37.1 months).No statistically significant difference was found in the clinicopathological characteristics between different EGFR expression types(P>0.05),while the best efficacy between different EGFR mutation groups was significantly different(P=0.040).Univariate analysis showed that EGFR mutation status in plasma ctDNA test was not correlated with PFS and OS of patients(P>0.05).Multivariate analysis showed that baseline lactate dehydrogenase(LDH)expression level,EGFR types,pleural effusion and the best curative effect might be independent factors of PFS.The patient’s N stage,bone metastasis,time to PFS and presence of EGFR T790M mutation might be independent predictors of OS.Conclusion:Icotinib as first-line treatment was effective in EGFR-mutant advanced NSCLC patients.The EGFR mutation status in plasma ctDNA test was not correlated with the clinical efficacy of patients.Bone metastasis was found to be an independent factor of worse prognosis.