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妇科肿瘤免疫检查点抑制剂临床应用指南

中华医学会妇科肿瘤学分会

中华医学会妇科肿瘤学分会. 妇科肿瘤免疫检查点抑制剂临床应用指南[J]. 协和医学杂志, 2021, 12(6): 854-880. doi: 10.12290/xhyxzz.2021-0683
引用本文: 中华医学会妇科肿瘤学分会. 妇科肿瘤免疫检查点抑制剂临床应用指南[J]. 协和医学杂志, 2021, 12(6): 854-880. doi: 10.12290/xhyxzz.2021-0683
Gynecological Oncology Society of Chinese Medical Association. Clinical Practice Guidelines for Immune Checkpoint Inhibitor Therapy in Gynecological Tumors[J]. Medical Journal of Peking Union Medical College Hospital, 2021, 12(6): 854-880. doi: 10.12290/xhyxzz.2021-0683
Citation: Gynecological Oncology Society of Chinese Medical Association. Clinical Practice Guidelines for Immune Checkpoint Inhibitor Therapy in Gynecological Tumors[J]. Medical Journal of Peking Union Medical College Hospital, 2021, 12(6): 854-880. doi: 10.12290/xhyxzz.2021-0683

妇科肿瘤免疫检查点抑制剂临床应用指南

doi: 10.12290/xhyxzz.2021-0683
详细信息

    通信作者:孔北华1,刘继红2,谢幸3,马丁4.
    1. 山东大学齐鲁医院妇产科,济南 250012,E-mail:kongbeihua@sdu.edu.cn
    2. 中山大学肿瘤防治中心妇科,广州 510060,E-mail:liujh@sysucc.org.cn
    3. 浙江大学医学院附属妇产科医院,杭州 310006,E-mail:xiex@zju.edu.cn
    4. 华中科技大学同济医学院附属同济医院妇产科,武汉 430030,E-mail:dma@tjh.tjmu.edu.cn

  • 中图分类号: R737.3; R730.53; R730.51

Clinical Practice Guidelines for Immune Checkpoint Inhibitor Therapy in Gynecological Tumors

More Information

    Corresponding authors: KONG Beihua1, LIU Jihong2, XIE Xing3, MA Ding4.
    1. Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, China, E-mail: kongbeihua@sdu.edu.cn
    2. Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China, E-mail: liujh@sysucc.org.cn
    3. Women's Hopital, School of Medicine Zhejiang University, Hangzhou 310006, China, E-mail: xiex@zju.edu.cn
    4. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China, E-mail: dma@tjh.tjmu.edu.cn

  • 摘要: 免疫检查点抑制剂(immune checkpoint inhibitor,ICI)在部分妇科恶性肿瘤患者中显示出一定的临床疗效,目前主要用于晚期和复发性癌经常规治疗失败的患者。在三大妇科恶性肿瘤中,以子宫内膜癌疗效最好,其次是子宫颈癌,卵巢癌疗效最差。对于复发耐药的滋养细胞肿瘤患者应用ICI治疗,部分患者可取得显著疗效。应用ICI治疗,应重视筛选治疗优势人群和合理的疗效评估,早期识别、及时干预免疫治疗相关不良事件。目前ICI单药治疗妇科肿瘤临床疗效有限,联合治疗有望提高其疗效。
    利益冲突:共识制订工作组所有参与人员均声明不存在利益冲突
    执笔专家组:
    孔北华,刘继红,周云,高庆蕾,宋坤,王登凤,陈丽莉,蒋芳,张国楠,向阳,谢幸,马丁
    编审专家组 (以姓氏笔画为序):
    万小平(上海市第一妇婴保健院),马丁(华中科技大学同济医学院附属同济医院),王丹波(辽宁省肿瘤医院),王世宣(华中科技大学同济医学院附属同济医院),王建六(北京大学人民医院),王登凤(四川省肿瘤医院/四川省第二人民医院),王新宇(浙江大学医学院附属妇产科医院),孔北华(山东大学齐鲁医院),曲芃芃(天津市中心妇产科医院),吕卫国(浙江大学医学院附属妇产科医院),向阳(中国医学科学院北京协和医院),刘继红(中山大学肿瘤防治中心),杨兴升(山东大学齐鲁医院),杨佳欣(中国医学科学院北京协和医院),吴小华(复旦大学附属肿瘤医院),吴令英(中国医学科学院肿瘤医院),汪辉(浙江大学医学院附属妇产科医院),沈铿(中国医学科学院北京协和医院),沈源明(浙江大学医学院附属妇产科医院),宋坤(山东大学齐鲁医院),张国楠(四川省肿瘤医院/四川省第二人民医院),陈刚(华中科技大学同济医学院附属同济医院),陈丽莉(浙江大学医学院附属妇产科医院),周云(中山大学肿瘤防治中心),赵霞(四川大学华西第二医院),哈春芳(宁夏医科大学/宁夏医科大学总医院),姜洁(山东大学齐鲁医院),徐丛剑(复旦大学附属妇产科医院),高庆蕾(华中科技大学同济医学院附属同济医院),高雨农(北京大学肿瘤医院),郭瑞霞(郑州大学第一附属医院),崔恒(北京大学人民医院),康山(河北医科大学第四医院),梁志清(陆军军医大学第一附属医院),蒋芳(中国医学科学院北京协和医院),程文俊(南京医科大学第一附属医院/江苏省人民医院),谢幸(浙江大学医学院附属妇产科医院)
  • 表  1  推荐级别及其代表意义

    推荐级别 代表意义
    1类 基于高级别临床研究证据,专家意见高度一致
    2A类 基于低级别临床研究证据,专家意见高度一致;或基于高级别临床研究证据,专家意见基本一致
    2B类 基于低级别临床研究证据,专家意见基本一致
    3类 不论基于何种级别临床研究证据,专家意见明显分歧
    下载: 导出CSV

    表  2  全球已批准上市的免疫检查点抑制剂(截至2021年9月1日)

    中文名称 英文通用名 免疫检查点 首次获批时间
    伊匹木单抗 ipilimumab CTLA-4 2011年(美国FDA)
    2013年(欧盟EMA)
    2021年(中国NMPA)
    帕博利珠单抗 pembrolizumab PD-1 2014年(美国FDA)
    2015年(欧盟EMA)
    2018年(中国NMPA)
    纳武利尤单抗 nivolumab PD-1 2014年(美国FDA)
    2017年(欧盟EMA)
    2018年(中国NMPA)
    阿替利珠单抗 atezolizumab PD-L1 2016年(美国FDA)
    2019年(欧盟EMA)
    2020年(中国NMPA)
    度伐利尤单抗 durvalumab PD-L1 2017年(美国FDA)
    2019年(中国NMPA)
    2020年(欧盟EMA)
    阿维鲁单抗 avelumab PD-L1 2017年(美国FDA)
    2017年(欧盟EMA)
    特瑞普利单抗 toripalimab PD-1 2018年(中国NMPA)
    信迪利单抗 sintilimab PD-1 2018年(中国NMPA)
    西米普利单抗 cemiplimab PD-1 2018年(美国FDA)
    2018年(欧盟EMA)
    卡瑞利珠单抗 camrelizumab PD-1 2019年(中国NMPA)
    替雷利珠单抗 tiselizumab PD-1 2019年(中国NMPA)
    dostarlimab-gxly PD-1 2021年(美国FDA)
    2021年(欧盟EMA)
    派安普利单抗 penpulimab PD-1 2021年(中国NMPA)
    赛帕利单抗 zimberelimab PD-1 2021年(中国NMPA)
    CTLA-4:细胞毒性T淋巴细胞相关抗原4;PD-1:程序性死亡[蛋白]-1;PD-L1:程序性死亡[蛋白]配体-1;FDA:食品药品监督管理局;EMA:欧洲药品管理局;NMPA:国家药品监督管理局
    下载: 导出CSV

    表  3  PD-1/PD-L1抑制剂单药治疗晚期/复发性子宫内膜癌的研究

    药物名称 研究(注册号) 试验期别 研究分组 样本量(n) 生物标志物(表达) ORR(%,95% CI)
    帕博利珠单抗 KEYNOTE-016 (NCT01876511)[26] Ⅱ期 单臂 15 dMMR 53
    KEYNOTE-158 (NCT02628067)[27] Ⅱ期 单臂 49 MSI-H/dMMR 57.1(42.2~71.2)
    KEYNOTE-028 (NCT02054806)[29] Ⅰb期 单臂 24 PD-L1 13(2.8~33.6)
    KEYNOTE-158 (NCT02628067)[28] Ⅱ期 单臂 82 TMB(15例TMB-H、67例非TMB-H) TMB-H:46.7非TMB-H:6.0
    纳武利尤单抗 NCI-MATCH Z1D亚组(NCT02465060)[30] Ⅱ期 单臂 13 dMMR 45.4
    JapicCTI-1632121*[34] Ⅱ期 单臂 22 PD-L1(8例阳性、14例阴性)/MSI(共检测8例,2例MSI-H、6例MSS) 总体:23(11~38)
    PD-L1阳性:25(7~54)
    PD-L1阴性:21(8~42)
    MSI-H:100(32~100)
    MSS:0(0~32)
    dostarlimab-gxly GARNET(NCT02715284)[31] Ⅰ期 单臂;
    队列dMMR
    队列pMMR
    dMMR:103
    pMMR:142
    MMR 队列A1:44.7(34.9~54.8)
    队列A2:13.4(8.3~20.1)
    阿替利珠单抗 NCT01375842#[35] Ⅰa期 单臂 15 PD-L1(5例阳性、10例阴性)/MSI(可评估8例,1例MSI-H、7例MSS) 13;PD-L1阳性者:40
    度伐利尤单抗 PHAEDRA/ANZGOG1601 (ACTRN12617000106336)[32] Ⅱ期 单臂;
    队列dMMR
    队列pMMR
    71
    dMMR:36
    pMMR:35
    MMR dMMR:47(32~63)
    pMMR:3(1~15)
    阿维鲁单抗 NCT02912572[33] Ⅱ期 单臂;
    队列dMMR
    队列pMMR
    dMMR:16
    pMMR:15
    MMR dMMR:26.7 (7.8~55.1)
    pMMR:6.3(0.2~30.2)
    药物名称 DCR(%, 95% CI) mDOR(月, 95% CI) mPFS(月, 95% CI) mOS(月, 95% CI)
    帕博利珠单抗 NA NA NA NA
    NA NR(2.9~27.0+) 25.7(4.9~NR) NR(27.2~NR)
    26 3例PR分别为63.7+周、64.7+周、64.3周
    SD者为24.6周(13.1~ 24.6)
    1.8(1.6~2.7) NR(4.3~NR)
    NA NA NA NA
    纳武利尤单抗 NA NA NA NA
    总体:68(52~81)
    PD-L1阳性:NA
    PD-L1阴性:NA
    MSI-H:NA
    MSS:NA
    总体:NE
    PD-L1阳性:NA
    PD-L1阴性:NA MSI-H:NA
    MSS:NA
    总体:3.4(2.0~5.4)
    PD-L1阳性:3.5(1.5~5.9)
    PD-L1阴性:3.3(2.0~9.1)
    MSI-H:NE
    MSS:2.2(1.4~4.0)
    总体:8.7(7.1~NE)
    PD-L1阳性:NA
    PD-L1阴性:NA
    MSI-H:NA
    MSS:NA
    dostarlimab-gxly 队列A1:57.3(47.2~67.0)
    队列A2:35.2(27.4~43.7)
    队列A1:NR
    队列A2:NR
    NA NA
    阿替利珠单抗 NA 2例PR者:7.3个月、8.1+个月 1.7(0.6~11+) 9.6(0.6~11.8+)
    度伐利尤单抗 NA NA dMMR:5.5
    pMMR:1.8
    dMMR:NR
    pMMR:11.5
    阿维鲁单抗 NA NA dMMR:4.4(1.7~NR)
    pMMR:1.9(1.6~2.8)
    dMMR:NR
    pMMR:6.6(2.0~10.2)
    *该研究为80%CI,PD-L1阳性:TPS≥1%;#PD-L1阳性,CPS≥5分;PD-1、PD-L1:同表 2;ORR:客观缓解率;DCR:疾病控制率;mDOR:中位缓解持续时间;mPFS:中位无进展生存期;mOS:中位总生存期;dMMR:错配修复缺陷;MSI-H:微卫星高度不稳定性;PR:部分缓解;SD:疾病稳定;TMB:肿瘤突变负荷;TMB-H:高肿瘤突变负荷;MSI:微卫星不稳定性;MSS:微卫星稳定性;pMMR:错配修复正常;MMR:错配修复;TPS:肿瘤细胞阳性比例分数;CPS:联合阳性评分;NA:无相关数据;NE:未评估;NR:未达到
    下载: 导出CSV

    表  4  PD-1/PD-L1抑制剂单药治疗晚期/复发性子宫颈癌的研究

    药物名称 研究(注册号) 试验期别 研究分组 样本量(n) 生物标志物(表达) ORR(%,95% CI)
    帕博利珠单抗 KEYNOTE-028(NCT02054806)[44] Ⅰb期 单臂 24 PD-L1阳性 17(5~37)
    KEYNOTE-158(NCT02628067)[45] Ⅱ期 单臂 98 PD-L1(82例阳性) 总体:12.2(6.5~20.4)
    PD-L1阳性:14.6(7.8~24.2)
    PD-L1阴性:0(0~21.8)
    纳武利尤单抗 JapicCTI-1632121*#[34] Ⅱ期 单臂 20 PD-L1(15例阳性、5例阴性)/MSI(共检测8例,0例MSI-H、8例MSS) 总体:25(13~41)
    PD-L1阳性:33(17~53)
    PD-L1阴性:0(0~37)
    MSI-H:NA
    MSS:25(7~54)
    CHECKMATE358(NCT02488759)#[46] Ⅰ/Ⅱ期 单臂 19 PD-L1(16例可评估,10例阳性、6例阴性) 26.3(9.1~51.2)
    NRG-GY002(NCT02257528)#[47] Ⅱ期 单臂 25 PD-L1(22例可评估,14例阳性、8例阴性) 4.0(0.4~22.9)
    赛帕利单抗 NCT03972722[48] Ⅱ期 单臂 41 PD-L1阳性 26.83(14.22~42.94)
    药物名称 DCR(%,95% CI) mDOR(月,95% CI) mPFS(月,95% CI) mOS(月,95% CI)
    帕博利珠单抗 30 5.4(4.1~7.5) 2(2~3) 11(4~15)
    总体:30.6(21.7~40.7)
    PD-L1阳性:32.9(22.9~44.2)
    PD-L1阴性:20(4.3~48.1)
    总体:NR
    PD-L1阳性:NR
    PD-L1阴性:NR
    总体:2.1(2.0~2.2)
    PD-L1阳性:2.1(2.1~2.3)
    PD-L1阴性:NA
    总体:9.4(7.7~13.1)
    PD-L1阳性:11(9.1~14.1)
    PD-L1阴性:NA
    纳武利尤单抗 总体:75(59~87)
    PD-L1阳性:NA
    PD-L1阴性:NA
    MSI-H:NA
    MSS:NA
    总体:NE(3.0~NE)
    PD-L1阳性:NA
    PD-L1阴性:NA
    MSI-H:NA
    MSS:NA
    总体:5.6(2.8~7.1)
    PD-L1阳性:5.5(2.8~7.1)
    PD-L1阴性:6.2(1.4~7.1)
    MSI-H:NA
    MSS:5.9(2.5~7.1)
    总体:NE(NE~NE)
    PD-L1阳性:NA
    PD-L1阴性:NA
    MSI-H:NA
    MSS:NA
    68.4(43.4~87.4) NR(23.3~29.5) 5.1(1.9~9.1) 21.9(15.1~NR)
    40 3.8 3.5(1.9~5.1) 14.5(8.3~26.8)
    赛帕利单抗 53.66(37.43~69.34) NA NA NA
    *该研究为80% CI,PD-L1阳性,TPS≥1%;#PD-L1阳性,TPS≥1%;PD-1、PD-L1:同表 2;ORR、DCR、mDOR、mPFS、mOS、MSI、MSI-H、MSS、TPS、NA、NE、NR: 同表 3
    下载: 导出CSV

    表  5  PD-1/PD-L1抑制剂联合治疗晚期/复发性子宫颈癌的研究

    联合方案 研究(注册号) 试验期别 研究分组 样本量(n) 生物标志物(表达) ORR(%, 95% CI)
    PD-1/PD-L1抑制剂联合含铂方案化疗
      紫杉醇/卡铂或顺铂(加或不加贝伐珠单抗)±帕博利珠单抗 KEYNOTE-826 (NCT03635567)[50] Ⅲ期 含铂化疗组,联合组(帕博利珠单抗联合含铂化疗) 617 (1∶1) CPS≥1分者548例,
    CPS≥10分者317例
    CPS≥1分者:联合组68.1、含铂化疗组50.2
    全部入组患者:联合组65.9、含铂化疗组50.8
    CPS≥10分者:联合组69.6、含铂化疗组49.1
    PD-1/PD-L1抑制剂联合CTLA-4抑制剂
      balstilimab±zalifrelimab NCT03104699,NCT03495882[51] Ⅱ期 balstilimab单药,balstilimab联合zalifrelimab 161,155 PD-L1:
    单药99例
    联合86例
    单药:14(10~21)
    PD-L1阳性:19(13~28)
    PD-L1阴性:10(4~22)
    联合:22(16~29)
    PD-L1阳性:27(19~37)
    PD-L1阴性:11(4~25)
      纳武利尤单抗+伊匹木单抗 CHECKMATE358 (NCT02488759)[52] Ⅰ/Ⅱ期 联合A:纳武利尤单抗3 mg/kg,每2周1次+伊匹木单抗1 mg/kg,每6周1次联合B:
    纳武利尤单抗1 mg/kg+伊匹木单抗3 mg/kg,每3周1次×4,随后纳武利尤单抗240 mg,每2周1次
    45
    46
    NA 联合A:既往化疗23,未化疗32
    联合B:既往化疗36,未化疗46
    PD-1/PD-L1抑制剂联合抗血管生成药物
      卡瑞利珠单抗+甲磺酸阿帕替尼# CLAP (NCT03816553)[53] Ⅱ期 单臂 45 PD-L1(40例可评估,30例阳性、10例阴性) 总体:55.6(40.0~70.4)
    PD-L1阳性:69.0
    PD-L1阴性:50.0
      卡瑞利珠单抗+苹果酸法米替尼 NCT03827837[54] Ⅱ期 单臂 18 NA 61.1(未经确认)
    50.5(确认)
      信迪利单抗+安罗替尼 ChiCTR1900023015[55] Ⅱ期 单臂 39 NA 61.5(44.9~75.9)
      阿替利珠单抗+贝伐珠单抗* NCT02921269[56] Ⅱ期 单臂 10 NA 0
    联合方案 DCR (%,95% CI) mDOR(月, 95% CI) mPFS(月, 95% CI) mOS(月, 95% CI)
    PD-1/PD-L1抑制剂联合含铂方案化疗
      紫杉醇/卡铂或顺铂(加或不加贝伐珠单抗)±帕博利珠单抗 NA CPS≥1分者:联合组18.0、含铂化疗组10.4全部入组患者:联合组18.0、含铂化疗组10.4 CPS≥10分者:联合组21.1、含铂化疗组9.4 CPS≥1分者:联合组10.4、含铂化疗组8.2(HR=0.62,95% CI:0.50~0.77,P < 0.001)
    全部入组患者:联合组10.4、含铂化疗组8.2(HR=0.65,95% CI:0.53~0.79,P < 0.001)
    CPS≥10分者:联合组10.4、含铂化疗组8.1(HR=0.58,95% CI:0.44~0.77,P < 0.001)
    CPS≥1分者:联合组24个月总生存率53.0%,含铂化疗组41.7%(HR=0.64,95% CI:0.50~0.81,P < 0.001)
    全部入组患者:联合组总生存率50.4%,含铂化疗组40.4%(HR=0.67,95% CI:0.54~0.84,P < 0.001)
    CPS≥10分者:联合组总生存率54.4%,含铂化疗组44.6%(HR=0.61,95% CI:0.44~0.84,P=0.001)
    PD-1/PD-L1抑制剂联合CTLA-4抑制剂
      balstilimab± zalifrelimab NA 单药:15.4(1.1+~15.4) 联合:NR(1.3+~16.6+) NA NA
      纳武利尤单抗+伊匹木单抗 NA NA 联合A:既往化疗3.6(1.9~5.1)
    未化疗13.8(2.1~NR)
    联合B:既往化疗5.8(3.5~17.2)
    未化疗8.5(3.7~NR)
    联合A:既往化疗10.3(7.9~15.2)
    未化疗NR(17.4~NR) 联合B:既往化疗25.4(17.5~NR)
    未化疗NR(13.9~NR)
    PD-1/PD-L1抑制剂联合抗血管生成药物
      卡瑞利珠单抗+甲磺酸阿帕替尼 82.2(67.9~92.0) NR(5.6~NE) 总体:8.8(5.6~NE)
    PD-L1阳性:NR(5.8~NE)
    PD-L1阴性:5.2(1.8~NE)
    NR(11.6~NE)
      卡瑞利珠单抗+苹果酸法米替尼 83.3 NA 12.3(3.2~NR) NA
      信迪利单抗+安罗替尼 94.9(80.7~98.8) NA NR NA
      阿替利珠单抗+贝伐珠单抗* 60 NA 2.9(1.8~6.0) 8.9(3.4~21.9)
    *未观察到经证实的临床缓解,mPFS仅为2.9个月,终止研究;#CPS≥1分;PD-1、PD-L1、CTLA-4:同表 2;ORR、CPS、DCR、mDOR、mPFS、mOS、NA、NE、NR: 同表 3
    下载: 导出CSV

    表  6  PD-1/PD-L1抑制剂单药治疗晚期/复发性卵巢癌的研究

    药物名称 研究(注册号) 试验期别 研究分组 样本量(n) 生物标志物(表达) ORR(%,95% CI)
    BMS-936559 NCT00729664[59] Ⅰ期 单臂 17 NA 6(0~29)
    纳武利尤单抗 UMIN000005714[60] Ⅱ期 单臂(铂耐药) 20 PD-L1(16例高表达,4例低表达) 15(3.2~37.9)
    NINJA (JapicCTI-153004)[61] Ⅱ期 纳武利尤单抗; 吉西他滨或PLD(铂耐药) 316 (1∶1) NA 纳武利尤单抗:7.6(3.5~13.9) 吉西他滨或PLD:13.2(7.6~20.8)
    帕博利珠单抗 KEYNOTE-028 (NCT02054806)[62] Ⅰb期 单臂 26 入组PD-L1者 11.5(2.4~30.2)
    KEYNOTE-100 (NCT02674061)*[63] Ⅱ期 单臂队列A:既往接受过1~3线治疗,PFI:3~12个月队列B:既往接受过4~6线治疗,PFI≥3个月 376队列A:285队列B:91 PD-L1队列A:CPS≥1分,101例CPS≥10分,43例队列B:CPS≥1分,49例CPS≥10分,22例 总体:8.5(5.9~11.8) CPS≥1分:8.0(4.2~13.6) CPS≥10分:13.8(6.5~24.7) 队列A:8.1(5.2~11.9) CPS≥1分:6.9(2.8~13.8) CPS≥10分:11.6(3.9~25.1) 队列B:9.9(4.6~17.9) CPS≥1分:10.2(3.4~22.2) CPS≥10分:18.2(5.2~40.3)
    阿替利珠单抗 NCT01375842# [64] Ⅰa期 单臂 10 NA 22.2(2.8~60.0)
    阿维鲁单抗 JAVELIN Solid Tumor (NCT01772004)[65] Ⅰb期 单臂 125 PD-L1 TPS≥1%:60.8% TPS≥5%:25.6% 肿瘤浸润免疫细胞≥10%:12.8% 9.6(5.1~16.2) TPS≥1%+/-:11.8/7.9 TPS≥5%+/-:12.5/9.8肿瘤浸润免疫细胞≥10%+/-:0/12.2
    JAVELIN Ovarian 200 (NCT02580058)[66] Ⅲ期 阿维鲁单抗单药; 阿维鲁单抗+PLD; PLD单药(铂耐药) 566 (1∶1∶1) NA 阿维鲁单抗单药:3.7(1.5~7.5) 阿维鲁单抗+PLD:13.3(8.8~19.0) PLD单药:4.2(1.8~8.1)
    药物名称 DCR(%, 95% CI) mDOR(月, 95% CI) mPFS(月, 95% CI) mOS(月, 95% CI)
    BMS-936559 24 NA NA NA
    纳武利尤单抗 45(23.1~68.5) NA 3.5(1.7~3.9) 20(7.0~NR)
    纳武利尤单抗:36.1吉西他滨或PLD:60.5 纳武利尤单抗:18.7(2.5~NE) 吉西他滨或PLD:7.4(3.0~10.3) 纳武利尤单抗:2.0(1.9~2.2) 吉西他滨或PLD:3.8(3.6~4.2) HR=1.5,P=0.002 纳武利尤单抗:10.1(8.3~14.1) 吉西他滨或PLD:12.1(9.3~15.3) HR=1.0,P=0.808(主要研究终点)
    帕博利珠单抗 38.4 NR(20.5+~30.4+) 1.9(1.8~3.5) 13.8(6.7~18.8)
    总体:22.1(18.0~26.6) CPS≥1分:24.0(17.4~31.6) CPS≥10分:27.7(17.3~40.2) 队列A:22.1(17.4~27.4) CPS≥1分:24.8(16.7~34.3) CPS≥10分:25.6(13.5~41.2) 队列B:22.0(14.0~31.9) CPS≥1分:22.4(11.8~36.6) CPS≥10分:31.8(13.9~54.9) 总体:10.2(3.3+~35.4+) 队列A:8.3(3.9~35.4+) 队列B:23.6(3.3+~32.8+) 队列A:2.1(2.1~2.2) CPS≥1分:2.1(2.1~2.8) CPS≥10分:2.1(2.1~4.2) 队列B:2.1(2.1~2.6) CPS≥1分:2.1(2.1~3.3) CPS≥10分:2.1(2.0~8.3) 队列A:18.7(17.0~22.5) CPS≥1分:20.6(15.2~23.2) CPS≥10分:21.9(12.9~26.8) 队列B:17.6(13.3~24.4) CPS≥1分:20.7(13.6~27.4) CPS≥10分:24.0(14.5~NR)
    阿替利珠单抗 22.2 2例PR者为8.1个月和30.6+个月 2.9(1.3~5.5) 11.3(5.5~27.7)
    阿维鲁单抗 52 NA 2.6(1.4~2.8) TPS≥1%+/-:2.7/1.4 TPS≥5%+/-:2.7/2.2肿瘤浸润免疫细胞≥10%+/-:1.5/2.6 11.2(8.7~15.4) TPS≥1%+/-:13.8/7.0 TPS≥5%+/-:10.6/11.9肿瘤浸润免疫细胞≥10%+/-:11.1/11.9
    阿维鲁单抗单药:33(26~40) 阿维鲁单抗+PLD:57(50~65) PLD单药:49(42~56) 阿维鲁单抗单药:9.2(8.4~NE) 阿维鲁单抗+PLD:8.5(5.8~NE) PLD单药:13.1(7.4~NE) 阿维鲁单抗单药:1.9(1.8~1.9) 阿维鲁单抗+PLD:3.7(3.3~5.1) PLD单药:3.5(2.1~4.0) 联合比PLD:HR=0.78 (93.1% CI:0.59~ 1.24),P=0.030阿维鲁单抗比PLD:HR=1.68(1.32~2.60),P>0.99 阿维鲁单抗单药:11.8(8.9~14.1) 阿维鲁单抗+PLD:15.7(12.7~18.7) PLD单药:13.1(11.8~15.5) 联合比PLD:HR=0.89,P=0.21阿维鲁单抗比PLD: HR=1.14(0.95~1.58),P=0.83
    *DCR,CR/PR/SD持续≥24周;#10例评估PFS/OS,9例评估ORR;PD-1、PD-L1:同表 2;ORR、DCR、mDOR、mPFS、mOS、PR、SD、TPS、CPS、NA、NE、NR: 同表 3;CR:完全缓解;PLD: 聚乙二醇化脂质体多柔比星;PFI: 无铂治疗间期
    下载: 导出CSV

    表  7  PD-1/PD-L1抑制剂联合化疗治疗晚期/复发性卵巢癌的研究

    联合方案 研究(注册号) 试验期别 研究分组 样本量(n) 生物标志物(表达) ORR(%, 95% CI)
    紫杉醇/卡铂±阿维鲁单抗 JAVELIN Ovarian 100 (NCT02718417)[67] Ⅲ期 化疗→Ave组:化疗随后阿维鲁单抗维持治疗;化疗+Ave→Ave组:化疗+阿维鲁单抗随后阿维鲁单抗维持;化疗→对照组:单独化疗随后观察(一线治疗) 998 (1∶1∶1) NA 化疗→Ave组:30.4(25.5~35.7)
    化疗+Ave→Ave组:36.0(30.8~41.4)
    化疗→对照组:30.4(25.6~35.7)
    PLD+阿维鲁单抗 JAVELIN Ovarian 200 (NCT02580058)[66] Ⅲ期 阿维鲁单抗单药;阿维鲁单抗+PLD;PLD单药(铂耐药) 566 (1∶1∶1) NA 阿维鲁单抗单药:3.7(1.5~ 7.5);
    阿维鲁单抗+PLD:13.3(8.8~19.0);
    PLD单药:4.2(1.8~8.1)
    PLD+度伐利尤单抗 NCT02431559[68] Ⅰ/Ⅱ期 单臂(铂耐药) 40 NA 22.5(10.8~38.5)
    PLD+帕博利珠单抗 NCT02865811[69] Ⅱ期 单臂(铂耐药) 23 NA 26.1(10.2~48.4)
    帕博利珠单抗+吉西他滨+顺铂 NCT02608684[70] Ⅱ期 单臂(铂耐药) 14 NA 61.1
    联合方案 DCR(%, 95% CI) mDOR(月, 95% CI) mPFS(月, 95% CI) mOS(月, 95% CI)
    紫杉醇/卡铂±阿维鲁单抗 NA NA 化疗→Ave组:16.8(13.5~NE);化疗+Ave→Ave组:18.1(14.8~ NE);化疗→对照组:NE(18.2~ NE);与化疗→对照组比较,PFS均未改善,超过了预定的无效界限,试验终止(主要研究终点) NA
    PLD+阿维鲁单抗 阿维鲁单抗单药:33(26~40)
    阿维鲁单抗+PLD:57(50~65)
    PLD单药:49(42~56)
    阿维鲁单抗单药:9.2(8.4~NE)
    阿维鲁单抗+PLD:8.5(5.8~NE)
    PLD单药:13.1(7.4~NE)
    阿维鲁单抗单药:1.9(1.8~1.9);
    阿维鲁单抗+PLD:3.7(3.3~5.1);
    PLD单药:3.5(2.1~4.0);
    联合比PLD:HR=0.78(93.1%CI:0.59~ 1.24),P=0.030;
    阿维鲁单抗比PLD:HR=1.68(1.32~2.60),P>0.99
    阿维鲁单抗单药:11.8(8.9~14.1);阿维鲁单抗+PLD:15.7(12.7~ 18.7);PLD单药:13.1(11.8~15.5);联合比PLD:HR=0.89,P=0.21;阿维鲁单抗比PLD:HR=1.14(0.95~ 1.58),P=0.83
    PLD+度伐利尤单抗 NA NA 5.5(0.3~28.8+) 17.6 (1.7~32.5+)
    PLD+帕博利珠单抗 CBR:52.2(30.6~73.2) (主要研究终点) NA 8.1(1.7~14.7) 18.3(9.4~31.5)
    帕博利珠单抗+吉西他滨+顺铂 88.9 4.9 6.2(3.78~8.26) 11.3(6.35~21.97)
    PD-1、PD-L1:同表 2;ORR、DCR、mDOR、mPFS、mOS、NA、NE: 同表 3;PLD: 同表 6;CBR: 临床获益率
    下载: 导出CSV

    表  8  PD-1/PD-L1抑制剂联合靶向药物治疗晚期/复发性卵巢癌的研究

    联合方案 研究(注册号) 试验期别 研究分组 样本量(n) 生物标志物(表达) ORR(%,95% CI)
    PD-1/PD-L1抑制剂联合CTLA-4抑制剂
      纳武利尤单抗±伊匹木单抗 NRG GY003 (NCT02498600)[71] Ⅱ期 纳武利尤单抗单药组,联合治疗组 100(1∶1) NA 纳武利尤单抗单药组:12.2联合治疗组:31.4(OR=3.28,85% CI:1.54~NE,P=0.034)
    PD-1/PD-L1抑制剂联合抗血管生成药物
      阿替利珠单抗+贝伐珠单抗 NCT01633970[72] Ⅰb期 单臂(铂耐药) 20 NA 15(3.2~37.9)
      纳武利尤单抗+贝伐珠单抗 NCT02873962[73] Ⅱ期 单臂 38(18例铂耐药,20例铂敏感) NA 总体#:28.9(15.4~45.9)
    铂耐药:16.7(3.6~41.4)
    铂敏感:40.0(19.1~64.0)
      帕博利珠单抗+仑伐替尼 LEAP-005 (NCT03797326)[74] Ⅱ期 单臂 31(25例铂耐药) NA 32(17~51)
      卡瑞利珠单抗+苹果酸法米替尼 NCT03827837[54] Ⅱ期 单臂(铂耐药) 32 NA 未确认:31.2
    确认:28.1
    PD-1/PD-L1抑制剂联合PARP抑制剂
      度伐利尤单抗+奥拉帕利 MEDIOLA (NCT02734004)[75] Ⅱ期 单臂(gBRCA突变的铂敏感) 32 NA 71.9 (53.25~86.25)
      帕博利珠单抗+尼拉帕利 TOPACIO/KEYNOTE-162 (NCT02657889)[76] Ⅰ/Ⅱ期 单臂(铂耐药) 60 NA 18(90% CI:11~29)
    多种治疗方式联合
      口服环磷酰胺+帕博利珠单抗+贝伐珠单抗 NCT02853318[77] Ⅱ期 单臂 40(30例铂耐药,10例铂敏感) NA 总体:47.5(90% CI:34.9~60.3)
    铂耐药:43.3(90% CI:29.6~58.2)
    铂敏感:60(90% CI:26.2~73.8)
      奥拉帕利+度伐利尤单抗±贝伐珠单抗 MEDIOLA (NCT02734004)[78] Ⅱ期 三药联合组,双药联合组(gBRCA野生型的铂敏感) 63(1∶1) NA 三药联合组:87.1(70.2~96.4)
    双药联合组:34.4(18.6~53.2)
      紫杉醇/卡铂±贝伐珠单抗±talazoparib±阿维鲁单抗 JAVELIN OVARIAN PARP 100 (NCT03642132) Ⅲ期 紫杉醇/卡铂联合贝伐珠单抗并序贯维持组,紫杉醇/卡铂化疗随后talazoparib维持组,紫杉醇/卡铂联合阿维鲁单抗并talazoparib+阿维鲁单抗序贯维持组(一线治疗) 720 (2.5∶1∶2.5) NA NA
      紫杉醇/卡铂+贝伐珠单抗±阿替利珠单抗 IMagyn050/GOG 3015/ENGOT-OV39(NCT03038100)[79] Ⅲ期 阿替利珠单抗联合组,对照组(一线治疗) 1301 (1∶1) PD-L1阳性* 阿替利珠单抗联合组:93(89~96)
    PD-L1阳性:92(87~96)
    对照组:89(84~92)
    PD-L1阳性:90(84~94)
    联合方案 DCR(%, 95% CI) mDOR(月, 95% CI) mPFS(月, 95% CI) mOS(月, 95% CI)
    PD-1/PD-L1抑制剂联合CTLA-4抑制剂
      纳武利尤单抗±伊匹木单抗 NA NA 纳武利尤单抗单药组:2.0联合治疗组:3.9(HR=0.528,0.339~0.821,P=0.004) 纳武利尤单抗单药组:21.8联合治疗组:28.1(HR=0.789,0.439~1.418,P=0.43)
    PD-1/PD-L1抑制剂联合抗血管生成药物
      阿替利珠单抗+贝伐珠单抗 55(31.5~76.9) NR(11.3~NR) 4.9(1.2~20.2) 10.2(1.2~26.6)
      纳武利尤单抗+贝伐珠单抗 总体:55.3
    铂耐药:33.3
    铂敏感:75
    NA 总体:9.4(6.7~NA)
    铂耐药:7.7(4.7~NA)
    铂敏感:12.1(8.4~NA)
    NA
      帕博利珠单抗+仑伐替尼 74(55~88) NR(1.5+~7.9+) 4.4(4.0~8.5) NA
      卡瑞利珠单抗+苹果酸法米替尼 62.5 NA 4.2(2.1~6.2) NA
    PD-1/PD-L1抑制剂联合PARP抑制剂
      奥拉帕利+度伐利尤单抗 28周DCR:65.6(90% CI:49.6~79.4) 10.2 11.1(8.2~15.9) NR
      尼拉帕利+帕博利珠单抗 65(90% CI:54~75) NA 3.4(2.1~5.1) NA
    多种治疗方式联合
      口服环磷酰胺+帕博利珠单抗+贝伐珠单抗 总体:95
    铂耐药:93.3
    铂敏感:100
    5.9(3.6~11.3) 总体:10.0(90% CI:6.5~17.4)
    铂耐药:7.6(90% CI:5.7~10.3)
    铂敏感:20.2(90% CI:6.0~NR)
    NA
      奥拉帕利+度伐利尤单抗±贝伐珠单抗 24周DCR(主要研究终点)
    三药联合组:77.4(90% CI:61.7~88.9)
    双药联合组:28.1(90% CI:15.5~43.9)
    三药联合组:11.1(IQR:7.4~16.4)
    双药联合组:6.9(IQR:5.4~11.1)
    三药联合组:14.7(10.0~18.1) 双药联合组:5.5(3.6~7.5) NA
      紫杉醇/卡铂±贝伐珠单抗±talazoparib±阿维鲁单抗 NA NA 联合维持组PFS无显著获益,研究中止
      紫杉醇/卡铂+贝伐珠单抗±阿替利珠单抗 NA NA 阿替利珠单抗联合组:19.5(18.1~20.8)
    PD-L1阳性:20.8(19.1~24.2)
    对照组:18.4(17.2~19.8)
    PD-L1阳性:18.5(16.6~21.4)
    mPFS两组间:HR=0.92(0.79~1.07),P=0.2785
    PD-L1阳性两组间:HR=0.80(0.65~0.99),P=0.0376(主要研究终点)(P≤0.002为阳性)
    阿替利珠单抗联合组:NE
    PD-L1阳性:NE
    对照组:NE PD-L1阳性:31.2(30.0~NE)
    mOS两组间:HR=0.96(0.74~1.26),P=0.7887
    PD-L1阳性两组间:HR=0.98(0.68~1.41), P=0.9083(OS中期分析)
    *浸润免疫细胞占肿瘤面积比例≥1%;#临床受益率为完全缓解、部分缓解和24周疾病无恶化的比例;RECIST 1.1评估;PD-1、PD-L1、CTLA-4 : 同表 2;ORR、DCR、mDOR、mPFS、mOS、NA、NE、NR: 同表 3;HR:风险比;RECIST:实体瘤临床疗效评价标准;IQR:四分位间距
    下载: 导出CSV

    表  9  免疫相关不良事件处理基本原则

    CTCAE分级 患者护理级别 激素 其他免疫检查点抑制剂 免疫治疗及后续应用
    G1 无需住院 不推荐 不推荐 继续
    G2 无需住院 局部激素或全身激素治疗,口服泼尼松或甲泼尼龙0.5~1.0 mg/(kg·d) 不推荐 暂时停用*
    G3 住院治疗 全身激素治疗,口服或静脉使用泼尼松或甲泼尼龙1~2 mg/(kg·d) 激素治疗3~5 d后症状未能缓解的患者可考虑在专科医生指导下使用 停用,基于患者的风险-获益比讨论是否恢复免疫治疗
    G4 住院治疗,考虑ICU 全身激素治疗,静脉使用甲泼尼龙1~2 mg/(kg·d),连续3 d,后逐渐减量至1 mg/(kg·d) 激素治疗3~5 d后症状未能缓解的患者可考虑在专科医生指导下使用 永久停用
    CTCAE:常见不良反应事件评价标准;ICU:重症监护病房;*如仅表现为皮肤或内分泌症状,免疫治疗可继续
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    附录1  妇科肿瘤常见irAE的分级和处理

    分级 描述 处理
    皮疹(检查全身皮肤、黏膜,评估既往皮肤疾病病史,必要时活检)
    G1 斑疹/丘疹区域 < 10%全身BSA,伴或不伴瘙痒、灼痛、紧绷等症状 继续ICI治疗;局部使用润肤剂;口服抗组胺药物;局部外用中效糖皮质激素
    G2 斑疹/丘疹区域占10%~30%全身BSA,伴或不伴瘙痒、灼痛、紧绷等症状,日常生活、使用工具能力受限 继续ICI治疗;局部使用润肤剂;口服抗组胺药物;局部外用中效或强效糖皮质激素和/或口服泼尼松0.5~1.0 mg/(kg·d)
    G3~G4 斑疹/丘疹区域>30%全身BSA,伴或不伴瘙痒、灼痛、紧绷等症状,日常生活自理能力受限 暂停ICI治疗;局部使用润肤剂;口服抗组胺药物;局部外用强效糖皮质激素,口服泼尼松0.5~1.0 mg/(kg·d),如无改善,增量至2 mg/(kg·d);请皮肤科会诊,必要时活检及住院治疗
    瘙痒(检查全身皮肤、黏膜,评估既往皮肤疾病病史)
    G1 轻微或局限 继续ICI治疗;口服抗组胺药物;局部外用中效糖皮质激素或利多卡因贴剂
    G2 剧烈或广泛;间歇性;抓挠至皮肤受损(如水肿、丘疹、脱屑、苔藓化、渗出/结痂);日常使用工具能力受限 加强止痒等对症处理时可继续ICI治疗(部分严重患者可考虑停用);口服抗组胺药物;局部外用强效糖皮质激素;请皮肤科会诊
    G3 强烈或广泛;持续性;日常生活自理能力明显受限或影响睡眠 暂停ICI治疗;口服抗组胺药物;泼尼松或甲泼尼龙0.5~1.0 mg/(kg·d);γ-氨基丁酸激动剂(如加巴喷丁、普瑞巴林);难治性瘙痒可考虑给予阿瑞匹坦或奥马珠单抗(如血IgE水平升高);请皮肤科会诊
    甲状腺功能减退
    G1 无症状,仅诊断性TFT,无需治疗 继续ICI治疗
    G2 有症状,需甲状腺激素替代治疗 继续ICI治疗;TSH升高(>10 mU/L),补充甲状腺素治疗;排除合并肾上腺功能不全;推荐专科会诊
    G3 严重症状,个人自理能力受限,需住院 同G2
    G4 危及生命,需紧急干预 暂停ICI治疗,对症支持治疗;推荐专科会诊
    甲状腺功能亢进
    G1 无症状,仅诊断性TFT,无需治疗 继续ICI治疗;有症状者,给予普萘洛尔、美替洛尔或阿替洛尔口服缓解症状;4~6周复查TFT;推荐专科会诊
    G2 有症状,需行甲状腺激素抑制治疗 同G1
    G3 严重症状,个人自理能力受限,需住院 同G1
    G4 危及生命,需紧急干预 暂停ICI治疗,对症支持治疗;推荐专科会诊
    肝脏毒性(注意排除病毒、疾病、其他药物等原因引起的肝功能异常)
    G1 AST或ALT < 3倍正常值上限(胆红素正常) 继续ICI治疗;增加肝功能监测频率
    G2 AST或ALT在3~5倍正常值上限(胆红素正常) 暂停ICI治疗;每3~5天复查肝功能;口服泼尼松0.5~1.0 mg/(kg·d),好转后缓慢减量,总疗程至少4周
    G3 AST或ALT在5~20倍正常值上限(胆红素正常) 永久性停用ICI;住院治疗;静脉滴注甲泼尼龙1~2 mg/(kg·d),待好转至G2后改等效口服并继续缓慢减量;每1~2天复查肝功能;请专科会诊;3 d无好转可考虑加用吗替麦考酚酯500~1000 mg,每12小时1次;不推荐使用英夫利西单抗
    G4 AST或ALT>20倍正常值上限(胆红素正常) 永久性停用ICI;住院治疗;静脉滴注甲泼尼龙2 mg/(kg·d);每天复查肝功能;请专科会诊;无禁忌时考虑肝脏活检;3 d无好转可考虑加用吗替麦考酚酯500~1000 mg,每12小时1次;不推荐使用英夫利西单抗
    其他 ALT或AST升高>G1,且胆红素>1.5倍正常值上限 永久性停用ICI;住院治疗;静脉滴注甲泼尼龙2 mg/(kg·d);每天复查肝功能;请专科会诊;3 d无好转可考虑加用吗替麦考酚酯500~ 1000 mg,每12小时1次;不推荐使用英夫利西单抗
    腹泻/结肠炎(大便检查排除感染性原因)
    G1 无症状,只需观察(1级腹泻 < 4次/d) 可继续ICI治疗;洛哌丁胺或地芬诺酯/阿托品2~3 d;行血常规、肝肾功能、电解质、TFT、大便检查等;必要时口服补液盐等对症处理,并密切监测病情变化;避免高纤维/乳糖饮食;如症状持续或加重,推荐乳铁蛋白检测,如阳性,按照下述G2处理,如阴性且无感染,继续G1治疗,加用美沙拉秦、考来烯胺
    G2 腹痛;大便带黏液或带血(2级腹泻4~6次/d) 暂停ICI治疗;检验项目同G1;有结肠炎体征时行胃肠X线检查;预约结肠镜、活检;口服泼尼松1~2 mg/(kg·d),如48~72 h无好转,考虑加用英夫利西单抗或维得利珠单抗(第1次使用英夫利西单抗或维得利珠单抗时应行结核检测)
    G3~G4 剧烈腹痛;大便习惯改变;需药物干预治疗;腹膜刺激征;影响日常生活能力;血流动力学不稳定;需住院治疗;或其他严重并发症(如肠缺血、肠坏死、中毒性巨结肠)(3级腹泻≥7次/d) G3暂停ICI治疗;G4永久性停用ICI;住院对症支持治疗;检验项目同G1;有结肠炎体征时行腹盆增强CT;预约结肠镜、活检;每天复查血常规、肝肾功能、电解质、C反应蛋白;饮食指导(禁食、流食、全肠外营养);静脉滴注甲泼尼龙1~2 mg/(kg·d),如48 h无好转,加用英夫利西单抗或维得利珠单抗
    肌炎或肌痛
    G1 轻度症状或不伴疼痛 继续ICI治疗;全面评估肌力;监测肌酸激酶、醛缩酶、转氨酶、乳酸脱氢酶等;如肌酸激酶升高并伴有肌力下降,可予以糖皮质激素治疗;排除禁忌后,可予以对乙酰氨基酚或非甾体抗炎药镇痛治疗
    G2 中度症状伴或不伴疼痛,影响使用工具能力 暂停ICI治疗;排除禁忌后,可予以对乙酰氨基酚或非甾体抗炎药镇痛治疗;监测肌酸激酶、醛缩酶、转氨酶、乳酸脱氢酶等;如肌酸激酶≥3倍正常值上限,予以口服泼尼松0.5~1.0 mg/(kg·d)
    G3 重度症状伴或不伴疼痛,影响日常生活自理能力 暂停ICI;请内分泌科、神经内科、风湿病科会诊;监测肌酸激酶、醛缩酶、转氨酶、乳酸脱氢酶等;静脉滴注甲泼尼龙1~2 mg/(kg·d)
    肺炎
    G1 无症状;局限于单个肺叶或 < 25%肺实质 考虑暂停ICI治疗;行胸部CT、血氧饱和度、血常规、肝肾功能、电解质、TFT、红细胞沉降率、肺功能等检查;3~4周复查胸部CT、肺功能;如影像学好转,密切随访并恢复ICI治疗;如影像学进展,升级治疗方案,暂停ICI治疗;如影像学无变化,继续治疗并密切随访至出现新症状
    G2 出现新症状或症状恶化,包括呼吸短促、咳嗽、胸痛、发热、缺氧;涉及多个肺叶且达到25%~ 50%肺实质,影响日常生活,需使用药物干预 暂停ICI治疗;请专科会诊;检查同上,并行感染性检查,如痰培养、血培养、支气管镜检查和支气管肺泡灌洗等排查感染;静脉滴注甲泼尼龙1~2 mg/(kg·d),治疗48~72 h后,若症状缓解,继续治疗并4~6周内逐步减量;若症状无好转,按照G3~G4治疗;如不能完全排除感染,经验性抗感染治疗;3~4周复查胸部CT;临床症状和影像学缓解至≤G1,可评估后使用ICI
    G3 严重的新发症状,累及所有肺叶或>50%肺实质,自理能力受限,需吸氧,需住院治疗 检查同G2;永久性停用ICI治疗;专科会诊;静脉滴注甲泼尼龙2 mg/(kg·d),酌情行肺通气治疗;治疗48 h后,若症状缓解,继续治疗至≤G1,然后在4~6周内逐步减量;若症状无好转,可考虑加用英夫利西单抗(5 mg/kg,静脉注射,必要时14 d后再次给药)或吗替麦考酚酯,或免疫球蛋白;如不能完全排除感染,需行抗感染治疗;必要时请呼吸科、感染科会诊
    G4 危及生命等呼吸困难、急性呼吸窘迫综合征,需气管插管等紧急干预治疗 同G3
    注:以上均为2A类推荐;irAE:免疫治疗相关不良事件;BSA:体表面积;ICI:免疫检查点抑制剂;IgE:免疫球蛋白E;TFT:甲状腺功能检测;TSH:促甲状腺激素;AST:谷草转氨酶;ALT:谷丙转氨酶
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    附录2  基线评估

    检查项目 评估内容
    一般情况 体格检查(包括神经系统检查);详细询问病史(包括自身免疫病、内分泌疾病、感染性疾病、吸烟史、家族史、妊娠史、既往治疗情况)和合并用药情况;排便习惯
    影像学检查 胸、腹(包括盆腔)CT或MRI;必要时脑MRI
    一般血液学检查 血常规;生化(包括血糖、血脂);感染性疾病筛查,如乙型肝炎、丙型肝炎、艾滋病等
    皮肤、黏膜 皮肤、黏膜检查,尤其是有免疫性皮肤疾病者
    甲状腺 甲状腺功能检测,包括促甲状腺激素、甲状腺素等
    肾上腺、垂体 肾上腺:早晨8点血浆皮质醇、促肾上腺皮质激素等检测;垂体:甲状腺功能检测
    氧饱和度(静息时和活动时);常规胸部影像学检查,如胸部CT;高危患者行肺功能检查
    心血管 心肌酶谱、心电图、心脏彩超(射血分数);必要时请心脏专科医生行个体化评估
    类风湿/骨骼肌 对有相关病史者进行关节检查、功能评估
    注:以上均为2A类推荐;MRI:磁共振成像
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    附录3  irAE监测

    检查项目 监测内容* 处理
    一般情况 每次随访时均应行irAE相关症状评估,包括体格检查(含神经系统检查)、排便习惯等 根据结果,予以相应处理
    影像学检查 ICI治疗期间,每4~6周复查胸、腹、盆腔CT 根据结果,予以相应处理
    一般血液学检查 ICI治疗期间,每次治疗前或每2~3周复查血常规、生化等;治疗结束后,每4~6周复查或病情需要时 根据结果,予以相应处理;血糖升高时,推荐检测糖化血红蛋白
    皮肤、黏膜 每次随访或查房时,行皮肤、黏膜检查,尤其是有自身免疫病者 及时记录(拍照)病变部位和类型,必要时活检
    甲状腺 ICI治疗期间,每4~6周复查TFT;治疗结束后,每12周复查或病情需要时 根据结果,予以相应处理
    肾上腺、垂体 ICI治疗期间,每次治疗前或每2~3周复查早晨8点的血浆皮质醇以及TFT#;治疗结束后,如无特殊情况,每6~12周复查 异常时,进一步检测促黄体生成素、促卵泡激素、雌二醇、促肾上腺皮质激素;根据结果,予以相应处理
    ICI治疗期间,每4~6周复查氧饱和度(静息时和活动时),以及常规肺部影像学检查,如胸部CT;必要时活检以排除其他原因 根据结果,予以相应处理
    心血管 ICI治疗期间,每2~4周复查心电图、心肌酶谱等,尤其是基线评估异常或有症状者 推荐咨询心脏专科医生进行相应处理
    注:以上均为2A类推荐;根据指征,必要时请相关专科会诊,转科治疗;*联合免疫治疗方案时酌情增加监测频率;#前4周期治疗后仅病情需要时复查;irAE、ICI、TFT:同附录1
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出版历程
  • 收稿日期:  2021-10-09
  • 录用日期:  2021-10-13
  • 网络出版日期:  2021-10-25
  • 刊出日期:  2021-11-30

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