非小细胞肺癌EGFR少见突变患者113例络氨酸激酶抑制剂疗效分析

Evaluation of EGFR-TKI treatment efficacy in non-small cell lung cancer patients with uncommon EGFR mutations

目的表皮生长因子受体(epidermal growth factor receptor,EGFR)突变是非小细胞肺癌(non-small cell lung cancer,NSCLC)最常见的激活突变。EGFR19缺失突变和EGFR21L858R突变约占所有EGFR突变的90%,被称为EGFR常见突变。这些突变对EGFR酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)的治疗高度敏感。其余的EGFR突变,也被称为EGFR少见突变,对于EGFR-TKI的应答表现出高度异质性,且TKI的疗效尚未完全明确。本研究旨在探讨EGFR-TKI对于不同类型的EGFR少见突变患者治疗的疗效,为进一步研究提供参考。方法回顾性分析2014-12-01-2018-11-30在中国科学技术大学附属第一医院就诊的113例携带少见EGFR突变的NSCLC患者临床资料。采用Kaplan-Meier法进行单因素生存分析以及Log-rank法进行单因素两水平比较。使用Cox比例风险模型进行多因素生存分析。结果 113例EGFR少见突变患者中女67例(59.3%),非吸烟者106例(93.8%),病理类型中腺癌109例(96.5%)。突变类型以单一突变为主(84例,74.3%)。EGFR20外显子插入突变对EGFR-TKI治疗的敏感性较低。奥西替尼似乎对原发T790M突变有一定的疗效。单一突变(7个月)和双突变(9.5个月)的患者在接受EGFR-TKI治疗后中位无进展生存期(progression free survival,PFS)差异无统计学意义,P=0.983。阿法替尼治疗EGFR少见突变(21外显子L861Q突变、18外显子G719X突变和20外显子S768I突变)患者的PFS为10个月(95%CI:6.76~13.23),明显长于1代EGFR抑制剂(7个月,95%CI:5.03~8.97)治疗的患者(HR=0.383,95%CI:0.175~0.837),P=0.01。多因素生存分析显示,TKI的使用(阿法替尼vs 1代EGFR-TKI)是影响PFS的唯一因素,HR=0.290,95%CI:0.108~0.780,P=0.014。结论 EGFR-TKI对于不同类型的EGFR少见突变的疗效有一定的差异。相比1代EGFR-TKI,阿法替尼可能是治疗EGFR少见突变(L861Q、G719X和S768I)更有效的药物。

OBJECTIVE Epidermal growth factor receptor(EGFR)mutations are the most frequently actionable mutations in non-small cell lung cancer(NSCLC).EGFRexon 19 deletions and EGFRexon 21 L858 Rmutations that account for approximately 90% of all EGFR mutations are known as common EGFR mutations and are highly sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs).Other EGFR mutations are termed uncommon EGFR mutations.The sensitivity of uncommon mutations to EGFR-TKIs exhibits highly heterogeneous and remains unclear.The purpose of this study was to evaluate the efficacy of EGFR-TKIs against different types of uncommon EGFR mutations,and to provide reference for more in-depth studies.METHODS This retrospective study included 113 primary NSCLC patients who had uncommon EGFR mutations at the First Affiliated Hospital of University of Science and Technology China from December 1 st,2014 to November 30 th,2018.Clinical data were collected and analyzed.The median PFS(progression free survival)was estimated using the Kaplan-Meier curves and statistically analyzed using the logrank test.The multivariate analysis was assessed using the Cox proportional model.RESULTS Of the 113 patients,female patients were 67(59.3%),Non-smokers were 106(93.8%).Adenocarcinoma was the most common histologic type(109,96.5%).Most of the patients(84,74.3%)had a single EGFR mutation.EGFRexon 20 insertion mutations exhibited poor response to EGFR TKI therapy.Osimertinib may be effective for primary T790 M mutation.There were no significant differences in PFS between patients with single uncommon EGFR mutations and those with double uncommon EGFR mutations(7 months vs 9.5 months;P=0.983).The median PFS of patients carrying uncommon EGFR mutations(L861 Q,G719 Xand S768 I)treated with afatinib was significantly higher than those treated with the first-generation EGFR-TKIs(10 months,95%CI:6.76-13.23 months vs 7 months,95%CI:5.03-8.96 months;P=0.01,HR=0.383,95%CI:0.175-0.837).The multivariate analysis showed that only EGFRtreatment(afatinib vs the first EGFRTKIs)was an independent predictor of PFS(HR=0.290,95%CI:0.108-0.780,P=0.014).CONCLUSIONS Different types of uncommon EGFRmutations showed variable response to EGFR-TKI treatment.Afatinib may be more effective than the first-generation EGFR-TKI for the treatment of NSCLC harboring uncommon mutations(L861 Q,G719 Xand S768 I).