TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究

杨明意 杨潇蓉 邓嘉怡 魏雪武 钟日威 周清

杨明意, 杨潇蓉, 邓嘉怡, 魏雪武, 钟日威, 周清. TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究[J]. 中国肿瘤临床, 2023, 50(10): 510-518. doi: 10.12354/j.issn.1000-8179.2023.20230131
引用本文: 杨明意, 杨潇蓉, 邓嘉怡, 魏雪武, 钟日威, 周清. TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究[J]. 中国肿瘤临床, 2023, 50(10): 510-518. doi: 10.12354/j.issn.1000-8179.2023.20230131
Mingyi Yang, Xiaorong Yang, Jiayi Deng, Xuewu Wei, Riwei Zhong, Qing Zhou. Responses to different therapies and the predictive markers of advancedEGFR-mutated non-small cell lung cancer after TKI resistance[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2023, 50(10): 510-518. doi: 10.12354/j.issn.1000-8179.2023.20230131
Citation: Mingyi Yang, Xiaorong Yang, Jiayi Deng, Xuewu Wei, Riwei Zhong, Qing Zhou. Responses to different therapies and the predictive markers of advancedEGFR-mutated non-small cell lung cancer after TKI resistance[J]. CHINESE JOURNAL OF CLINICAL ONCOLOGY, 2023, 50(10): 510-518. doi: 10.12354/j.issn.1000-8179.2023.20230131

TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究

doi: 10.12354/j.issn.1000-8179.2023.20230131
基金项目: 本文课题受国家自然科学基金(编号:82072562)、广东省人民医院(广东省医学科学院)“登峰计划:高水平医院建设项目”科研专项(编号:DFJH201810)资助
详细信息
    作者简介:

    杨明意:专业方向为晚期肺癌免疫治疗生物标志物研究

    通讯作者:

    周清 gzzhouqing@126.com

Responses to different therapies and the predictive markers of advancedEGFR-mutated non-small cell lung cancer after TKI resistance

Funds: The work was supported by the National Natural Science Foundation of China (No. 82072562) and the High level Hospital Construction Project (No. DFJH201810)
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  • 摘要:   目的  评估TKI耐药后晚期EGFR突变型非小细胞肺癌(non-small cell lung cancer,NSCLC)在真实世界中化疗、化疗联合抗血管和免疫治疗的临床疗效以及最佳免疫治疗联合方案和探讨优势人群临床病理特征。  方法  回顾性分析2014年1月至2022年10月于广东省人民医院肿瘤医院收治229例TKI耐药后晚期EGFR突变型NSCLC患者的临床病理资料。本研究将纳入的患者分为非ICI治疗组(化疗和化疗联合抗血管)122例,ICI治疗组(含免疫治疗)107例,分析患者临床特征与治疗疗效之间的关系。  结果  纳入患者非ICI治疗组和ICI治疗组的中位无进展生存期(progression-free survival,PFS)分别为5.2个月和5.2个月(P=0.129),中位生存期(overall survival,OS)分别为18.2个月和14.1个月(P=0.026)。进一步分析107例ICI治疗组,使用化疗联合免疫治疗、化疗联合抗血管联合免疫治疗和免疫单药或抗血管联合免疫治疗的中位PFS分别为5.6、6.7和2.3个月(P=0.074),中位OS分别为15.5、18.6和8个月(P=0.165)。PD-L1表达≥50%患者的中位PFS和中位OS较PD-L1表达<50%患者明显延长(中位PFS:5.6个月vs. 5.0个月,P=0.040;中位OS:19.2个月vs. 12.6个月,P=0.046)。  结论  晚期EGFR突变型NSCLC患者TKI耐药后四药联合免疫治疗似乎呈现出更好的生存获益趋势,PD-L1表达是预测该人群免疫治疗获益的生物标志物。

     

  • 图  1  TKI耐药后晚期EGFR突变型NSCLC对不同治疗的生存分析

    A:中位PFS; B:中位OS;C:中位PFS;D:中位OS

    图  2  不同免疫治疗方案对TKI耐药后晚期EGFR突变型NSCLC的生存分析比较

    A:PFS;B:OS

    图  3  TKI耐药后晚期EGFR突变型NSCLC接受ICI治疗疗效与PD-L1表达的相关性

    A:PD-L1表达≥50%对比PD-L1表达<50%的PFS比较;B:PD-L1表达≥50%对比PD-L1表达<50%的OS比较

    表  1  患者的基线情况

    特征总体(n=229)非ICI治疗组(n=122)ICI治疗组(n=107)
    性别
     男性108(47.2)58(47.5)50(46.7)
     女性121(52.8)64(52.5)57(53.3)
    是否吸烟
     是56(24.5)32(26.2)24(22.4)
     否173(75.5)90(73.8)83(77.6)
    免疫或化疗前分期(期)
     ⅣA41(17.9)24(19.7)17(15.9)
     ⅣB188(82.1)98(80.3)90(84.1)
    免疫或化疗前病理类型
     腺癌226(98.7)122(100)104(97.2)
     鳞癌3(1.3) 0(0.0)3(2.8)
    免疫或化疗前转移病灶
     胸腔转移或胸腔积液149(65.1)81(66.4)68(63.6)
     脑转移101(44.1)51(41.8)50(46.7)
     肝转移62(27.1)27(22.1)35(32.7)
    免疫或化疗前PS评分(分)
     0~1217(94.8)120(98.4)97(90.7)
     212(5.2)2(1.6)10(9.3)
    基因突变类型
     EGFR19del106(46.3)56(45.9)50(46.7)
     EGFR21L858R115(50.2)62(50.8)53(49.5)
     其他8(3.5)4(3.3)4(3.8)
    PD-L1表达
     <50%119(52.0)66(54.1)53(49.5)
     ≥50%57(24.9)20(16.4)37(34.6)
     未知53(23.1)36(29.5)17(15.9)
    免疫或化疗前是否出现T790M突变
     是79(34.5)44(36.1)35(32.7)
     否150(65.5)78(63.9)72(67.3)
    免疫或化疗前是否手术
     是53(23.1)22(18.0)31(29.0)
     否176(76.9)100(82.0)76(71.0)
    免疫或化疗前是否放疗(肺部病灶)
     是20(8.7)8(6.6)12(11.2)
     否209(91.3)114(93.4)95(88.8)
    是否使用过奥希替尼
     是155(67.7)74(60.7)81(75.7)
     否74(32.3)48(39.3)26(24.3)
    奥希替尼使用线数(线)
     074(32.3)48(39.3)26(24.3)
     131(13.5)13(10.7)18(16.8)
     ≥2124(54.2)61(50.0)63(58.9)
    治疗前是否使用过化疗
     是96(41.9)17(13.9)79(73.8)
     否133(58.1)105(86.1)28(26.2)
    治疗线数(线)
     <4120(52.4)87(71.3)33(30.8)
     ≥4109(47.6)35(28.7)74(69.2)
    是否联合抗血管生成治疗
     是132(57.6)88(72.1)43(40.2)
     否97(42.4)34(27.9)64(59.8)
    ()内单位为%;“免疫或化疗前转移病灶”定义为患者只要出现了对应某个器官的转移就可纳入分析。患者可能会同时出现多个器官转移,例数合计非百分百
    下载: 导出CSV

    表  2  TKI耐药后晚期EGFR突变型NSCLC对不同治疗的疗效

    项目总体(n=229)ICI治疗组(n=107)非ICI治疗组(n=122)
    DCR160(69.9)75(70.1)85(69.7)
    ORR67(29.3)30(28.0)37(30.3)
    PD42(18.3)20(18.7)22(18.0)
    PR67(29.3)30(28.0)37(30.3)
    SD93(40.6)45(42.1)48(39.4)
    UK27(11.8)12(11.2)15(12.3)
    ()内单位为%
    下载: 导出CSV

    表  3  TKI耐药后晚期EGFR突变型NSCLC接受免疫治疗的临床病理特征

    特征总体(n=107)化疗+抗血管+免疫(n=38)化疗+免疫(n=43)抗血管+免疫或免疫单药(n=26)
    性别
     男性50(46.7)14(36.8)20(46.5)16(61.5)
     女性57(53.3)24(63.2)23(53.5)10(38.5)
    是否吸烟
     是24(22.4)6(15.8)10(23.3)8(30.8)
     否83(77.6)32(84.2)33(76.7)18(69.2)
    免疫前分期(期)
     ⅣA17(15.9)3(7.9)7(16.3)7(26.9)
     ⅣB90(84.1)35(92.1)36(83.7)19(73.1)
    免疫前病理类型
     腺癌104(97.2)38(100)41(95.3)25(96.2)
     鳞癌3(2.8) 0(0.0)2(4.7)1(3.8)
    免疫前转移病灶
     胸腔转移或胸腔积液68(63.6)22(57.9)28(65.1)18(69.2)
     脑转移50(46.7)20(52.6)20(46.5)10(38.5)
     肝转移35(32.7)14(36.8)10(23.3)11(42.3)
    免疫前PS评分(分)
     0~197(90.7)37(97.4)38(88.4)22(84.6)
     210(9.3)1(2.6)5(11.6)4(15.4)
    基因突变类型
     EGFR19del50(46.7)18(47.4)19(44.2)13(50.0)
     EGFR21L858R53(49.5)19(50.0)21(48.8)13(50.0)
     其他4(3.8)1(2.6)3(7.0) 0(0.0)
    PD-L1表达
     <50%53(49.5)20(52.6)21(48.8)12(46.2)
     ≥50%37(34.6)9(23.7)17(39.5)11(42.3)
     未知17(15.9)9(23.7)5(11.7)3(11.5)
    免疫前是否出现T790M突变
     是35(32.7)14(36.8)14(32.6)7(26.9)
     否72(67.3)24(63.2)29(67.4)19(73.1)
    免疫前是否手术
     是31(29.0)14(36.8)11(25.6)6(23.1)
     否76(71.0)24(63.2)32(74.4)20(76.9)
    免疫前是否放疗(肺部病灶)
     是12(11.2)7(18.4)4(9.3)1(3.8)
     否95(88.8)31(81.6)39(90.7)25(96.2)
    是否使用过奥希替尼
     是81(75.7)33(86.8)32(74.4)16(61.5)
     否26(24.3)5(13.2)11(25.6)10(38.5)
    奥希替尼使用线数(线)
     026(24.3)5(13.2)11(25.6)10(38.5)
     118(16.8)5(13.2)11(25.6)2(7.7)
     ≥263(58.9)28(73.6)21(48.8)14(53.8)
    免疫前是否使用过化疗
     是79(73.8)30(78.9)28(65.1)21(80.8)
     否28(26.2)8(21.1)15(34.9)5(19.2)
    治疗线数(线)
     ≥474(69.2)31(81.6)28(65.1)15(57.7)
     <433(30.8)7(18.4)15(34.9)11(42.3)
    ()内单位为%
    下载: 导出CSV

    表  4  不同免疫治疗方案对TKI耐药后晚期EGFR突变型NSCLC的疗效分析

    项目总体
    n=107)
    化疗+抗血管+
    免疫
    n=38)
    化疗+免疫
    n=43)
    抗血管+免疫或
    免疫单药
    n=26)
    DCR75(70.1)33(86.8)31(72.1)11(42.3)
    ORR30(28.0)13(34.2)12(27.9)5(19.2)
    PD20(18.7)2(5.3)6(14.0)12(46.2)
    PR30(28.0)13(34.2)12(27.9)5(19.2)
    SD45(42.1)20(52.6)19(44.2)6(23.1)
    UK12(11.2)3(7.9)6(14.0)3(11.5)
    ()内单位为%
    下载: 导出CSV

    表  5  影响TKI耐药后晚期EGFR突变型NSCLC免疫治疗预后的Cox多因素回归分析

    临床特征OS多因素分析PFS多因素分析
    HR(95%CI)PHR(95%CI)P
    性别(女性 vs. 男性)1.90(1.10~3.29)0.0221.65(1.03~2.63)0.038
    免疫前PS评分(2分 vs. 0~1分)2.41(1.06~5.46)0.0360.491
    PD-L1表达(≥50% vs. <50%)0.1170.54(0.32~0.92)0.023
    治疗线数(<4线 vs. ≥4线)2.11(1.09~4.05)0.0260.220
    单药/联合(单药 vs. 联合)0.2150.53(0.30~0.93)0.028
    下载: 导出CSV
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  • 收稿日期:  2023-02-16
  • 录用日期:  2023-04-07
  • 修回日期:  2023-04-05

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