河北省晚期食管鳞癌免疫治疗现状及进展
作者简介:
段晓阳，女，博士，主治医师，主要从事食管癌、胃癌、肺癌等内科治疗的研究，ORCID: 0000-0001-7069-6005
史健: 主任医师，教授，医学博士，博士生导师。河北省肿瘤内科质量控制与管理中心主任，河北省临床研究质量评价和促进中心副主任，河北医科大学第四医院肿瘤内科主任，美国安德森癌症中心访问学者，国家二级心理培训师，国家二级公共营养师。河北省石家庄市政协委员，河北省石家庄市长安区人民代表大会委员，河北省检察院听证员，九三学社石家庄市委妇女专委会副主任，九三学社河北医科大学第四医院支社主委，河北省社会保障厅省管评审专家，河北、江西、河南、广东、重庆、山东省科技奖励专家库专家，教育部学位中心评审专家博硕学位论文评审专家。中国初级卫生保健基金会基层肿瘤防治专业委员会副主任委员，中国医药教育协会临床研究培训基地副主任委员，中国中药协会肿瘤药物研究专业委员会常务委员，中国医药教育协会疑难肿瘤专业委员会常务委员，中国医药教育协会腹部肿瘤专业委员会快速康复学组常务委员，中国抗癌协会肿瘤音乐干预专业委员会常务委员。河北省抗癌协会多原发和不明原发肿瘤专委会主任委员，河北省医师协会肿瘤科医师分会候任主委，河北省女医师协会肿瘤内科专委会主任委员，河北省针灸协会穴位贴敷专业委员会主委。主持科技部课题1项，参与国家自然基金课题3项；主持科技部课题1项，河北省自然基金课题2项，河北省科技厅课题8项，参研课题15项。获得中国抗癌协会科技奖三等奖一项，河北科学技术进步奖二等奖、文章三等奖各一项，河北医学技术奖一等奖三项。发表SCI相关专业文章和国内专业核心期刊文章100余篇。主编著作4部，副主编1部
。
通讯作者:
Research Status and Progress on Immunotherapy for Advanced Esophageal Squamous Cell Carcinoma in Hebei Province
-
摘要:
食管鳞状细胞癌是河北省最常见的消化道恶性肿瘤之一，因早期症状不典型，多数患者确诊时已为晚期，不适合手术治疗，多采用内科综合治疗，但治疗效果欠佳，预后差。近年来，免疫治疗的出现给晚期食管鳞癌患者带来了希望，较大程度地改善了患者预后，但仍存在免疫耐药、疗效预测指标选择、优势人群筛选、联合治疗策略的选择等困惑。因此，基于河北省食管鳞癌的高发病率及预后差情况，本文将对晚期食管鳞癌治疗的研究进展进行简要综述，希望为晚期食管癌的治疗策略提供参考。
Abstract:Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal cancers in Hebei province. Most patients are diagnosed at an advanced stage due to untypical early symptoms, making surgical treatment often unfeasible. As a result, most of them are treated with comprehensive medical treatment, which tends to have limited effectiveness and poor prognosis. However, the recent introduction of immunotherapy has considerably advanced treatment options for patients with advanced ESCC, notably improving their prognosis. Uncertainties regarding immune resistance, the selection of predictive indicators of efficacy, the identification of dominant population, and the choice of combined treatment strategies are still evident. Therefore, based on the high incidence and poor prognosis of ESCC in Hebei Province, this article will briefly review the research progress in the treatment of advanced ESCC, aiming to provide guidance for treatment strategies for advanced esophageal cancer.
-
Key words:
- Esophageal squamous cell carcinoma /
- Immunotherapy /
- Research progress
-
0 引言
食管癌（Esophageal cancer, EC）是全球最常见的消化道恶性肿瘤之一。据2022年全球癌症统计报告，食管癌新发病例51.07万（占总新发病例2.6%），死亡人数约44.51万（占癌症死亡总数4.6%），发病率和病死率分别位居全球恶性肿瘤第11位和第7位[1]。中国食管癌发病率和死亡率均超过全球的平均值[2]，其中河北省是食管癌的高发地区，食管鳞癌（Esophageal squamous cell carcinoma, ESCC）为其主要发病类型，因早期发病隐匿，多数患者确诊时已为晚期，尽管免疫治疗方法在晚期食管鳞癌一线及后线的治疗已经确定，但仍存在免疫耐药、免疫治疗不良反应等问题，导致患者疗效欠佳，预后差。因此，本文将针对河北省晚期食管鳞癌免疫治疗的研究及热点问题进行总结及展望，为临床食管鳞癌治疗策略提供更多参考依据。
1 河北省食管癌的流行病学
20世纪70年代，我国河南林县、河北磁县、涉县及山西阳城县是食管癌的高发地区。其中河北磁县的发病率和死亡率均为全国平均水平的5~8倍[3]，严重威胁人民生命健康。在过去的50年，河北省食管癌死亡率呈下降趋势，2018年食管癌世标死亡率较1973—1975年下降83.65%[4]。《2023河北省肿瘤登记年报》数据[5]显示，河北省食管癌的发病率为14.41/10万，新发病例约
9540 例。其中城市和农村发病率分别为9.18/10万和17.40/10万，农村发病率是城市的1.90倍。同期食管癌的死亡率为12.03/10万，城市死亡率为8.23/10万，农村死亡率为14.21/10万，农村是城市的1.73倍。河北省食管癌的病理类型87.93%为ESCC，其余为食管腺癌（Esophageal adenocarcinoma, EAC）和其他[6]。研究发现，磁县食管癌高发区水中硝酸盐氮和亚硝酸盐氮含量较高、食用高脂肪食物、腌制蔬菜、发霉食品等也和食管癌的发生相关，饮食过烫、食用速度过快可能是诱因之一[7-8]。通过对以食管癌为重点癌种的三级综合防控、发生发展机制的研究、医疗检查技术及新药的不断进展，河北省食管癌发病率和死亡率显著下降，但5年生存率仍较低[9]，近几年，免疫治疗的出现打破了晚期食管鳞癌的治疗瓶颈，患者疗效显著提高，生存延长，成为当前研究的热点。2 免疫治疗在恶性肿瘤中的作用机制
在肿瘤的发生和发展中，免疫系统的抑制和重新编程起着关键作用。免疫治疗的目的是重新激活抗肿瘤免疫细胞，克服肿瘤的免疫逃逸机制。研究最多的是针对PD-1/PD-L1和CTLA-4/B7-1/2这两个免疫检查点通路的抑制剂来增强机体免疫系统的特异性抗肿瘤作用[10]。PD-1是CD28受体家族的成员之一，是一种共抑制受体，在T细胞上高表达，能抑制T淋巴细胞的功能，这对控制自身免疫反应至关重要。PD-1的配体PD-L1（最初被确定为B7-H1），在多种类型的癌细胞上高度表达，可与PD-1结合并介导肿瘤的免疫逃逸。因此，PD-1抑制剂可以特异性与PD-1结合，减弱对T淋巴细胞的免疫抑制，使T淋巴细胞能够杀伤肿瘤细胞[11-12]。临床常用的PD-1/PD-L1抑制剂有帕博利珠单抗（Pembrolizumab）、纳武利尤单抗（Nivolumab）、卡瑞利珠单抗 （Camrelizumab）、信迪利单抗（Sintilimab）、阿替利珠单抗（Atezolizumab）等。CTLA-4（CD152）是一种跨膜蛋白，在活化的CD4+和CD8+T细胞中表达，可以和CD80/CD86结合抑制T细胞的激活，引起肿瘤细胞的免疫逃逸。因此，阻断CTLA-4可以下调效应性T细胞的抑制信号，减少Tregs的抑制作用，从而提高T细胞的抗肿瘤作用。临床常用药物有伊匹木单抗（Ipilimumab），可阻断CTLA-4来增强抗肿瘤作用[13-14]。
3 免疫治疗在晚期食管鳞癌一线治疗的研究进展
免疫治疗的出现为晚期ESCC的治疗带来了巨大的突破，多项临床研究已证实一线免疫联合化疗方案的疗效和安全性，成为晚期ESCC治疗的新标准。截至目前，根据KEYNOTE-590[15]、CHECKMATE-648[16]、ESCORT-1st[17]、JUPITER-06[18]、ORIENT-15[19]、RATIONALE 306[20]、ASTRUM-007[21] 、GEMSTONE-304[22]八个大型随机对照研究结果显示，进口的帕博利珠单抗、纳武利尤单抗及国产的卡瑞利珠单抗、特瑞普利单抗、信迪利单抗、替雷利珠单抗、斯鲁利单抗共七个PD-1抑制剂及舒格利单抗一个PD-L1抑制剂在分别联合化疗一线治疗晚期ESCC的疗效优于传统双药化疗方案，因此，免疫联合化疗成为了ESCC诊疗指南的Ⅰ级推荐方案（1A类），成为晚期ESCC一线治疗的新标准，具体研究内容及结果见表1。
表 1 晚期ESCC一线免疫治疗的Ⅲ期研究Table 1 Phase Ⅲ study of first-line immunotherapy for advanced ESCCTrials Sample
sizesTreatments ORR(%) mPFS(m) mOS(m) ≥Grade 3 adverse
reactions (%)Keynote-590
(All groups)373/376 Pembrolizumab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)45.0 vs. 29.3 6.3 vs. 5.8
HR=0.65
95%CI:
(0.55–0.76)12.4 vs. 9.8
HR=0.73
95%CI:
(0.62–0.86)71.9 vs. 67.6 Keynote-590
(China)51/55 Pembrolizumab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)37.3 vs. 20.0 6.2 vs. 4.6
HR=0.60
95%CI:
(0.39–0.92)10.5 vs. 8.0
HR=0.51
95%CI:
(0.32–0.81)74.5 vs. 66.7 Checkmate-648 321/324 Nivolumab+
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)47.0 vs. 27.0 5.8 vs. 5.6
HR=0.83
95%CI:
(0.68–1.00)12.8 vs. 10.7
HR=0.78
95%CI:
(0.65–0.93)49.0 vs. 36.0 RATIONALE-306 326/323 Tislelizumab +
chemo (ptx + cis/cis + 5-Fu)
vs. chemo (ptx + cis/cis + 5-Fu)63.5 vs. 42.4 7.3 vs. 5.6
HR=0.62
95%CI:
(0.52–0.75)17.2 vs. 10.6
HR=0.66
95%CI:
(0.54–0.80)67.0 vs. 64.0 ESCORT-1st 298/297 Camrelizumab +
chemo (ptx + cis)
vs. chemo (ptx + cis)72.1 vs. 62.1 6.9 vs. 5.6
HR=0.56
95%CI:
(0.46–0.68)15.3 vs. 12
HR=0.70
95%CI:
(0.56–0.88)63.4 vs. 67.7 ORIENT-15 327/332 Sintilimab + chemo (ptx +
cis / 5-FU + cis)vs.
chemo (ptx + cis/5-FU + cis)66.1 vs. 45.5 7.2 vs. 5.7
HR=0.56
95%CI:
(0.46–0.68)17.4 vs. 12.8
HR=0.66
95%CI:
(0.55–0.79)59.9 vs. 54.5 JUPITER-06 257/257 Toripalimab +
chemo (ptx + cis)
vs. chemo (ptx + cis)69.3 vs. 52.1 5.7 vs. 5.5
HR=0.58
95%CI:
(0.46–0.74)17 vs. 11
HR=0.58
95%CI:
(0.43–0.78)64.6 vs. 56.0 ASTRUM-007 368/183 Serplulimab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)57.6 vs. 42.1 5.8 vs. 5.3
HR=0.60
95%CI:
(0.48–0.75)15.3 vs. 11.8
HR=0.68
95%CI:
(0.53–0.87)64.0 vs. 59.0 GEMSTONE-304 358/182 Sugemalimab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)60.1 vs. 45.2 6.2 vs. 5.4
HR=0.67
95%CI:
(0.54–0.82)15.3 vs. 11.5
HR=0.70
95%CI:
(0.55–0.90)51.3 vs. 48.4 Notes: ESCC: esophageal squamous cell carcinoma; Chemo: chemotherapy; cis: cisplatin; 5-FU: 5-Fluorouracil; ptx: paclitaxel; ORR: objective response rate; mPFS: median progression-free survival; mOS: median overall survival; HR: hazard ratio. 尽管免疫联合化疗方案为晚期ESCC患者带来的生存获益提高，但仍不满足目前临床的需要，鉴于晚期ESCC患者仅一次最佳初治的时机，为获得更好的疗效，满足更多患者的个体化精准治疗，因此，对晚期ESCC患者初始治疗方案的探索尤为重要。目前晚期ESCC一线治疗方案探索方向有以下两方面。
一是在免疫联合化疗基础上，增加其他类型药物来增强疗效，比如血管内皮生长因子酪氨酸激酶抑制剂、TIGIT抗体等药物。LEAP-014研究是评估仑伐替尼+帕博利珠单抗+化疗在未经治疗的转移性ESCC患者的疗效和安全性的Ⅲ期临床研究，第一阶段的研究结果显示了在免疫联合化疗基础上增加仑伐替尼的治疗方案安全性是可耐受的[23]。同样，在一项安罗替尼联合卡瑞利珠单抗联合紫杉醇和卡铂一线治疗晚期ESCC疗效和安全性的Ⅱ期研究中[24]，结果显示在免疫联合化疗中加入安罗替尼后客观缓解率（Objective response rate, ORR）为90%，疾病控制率（Disease control rate, DCR）为100%，中位无进展生存期（Progression-free survival, PFS）达13.4个月，未发生4级或5级不良反应，整体安全性可控。TQB2450-II-13研究[25]为安罗替尼联合贝莫苏拜单抗（PD-L1抑制剂）+化疗一线治疗转移性ESCC的疗效和安全性研究，结果显示，安罗替尼联合免疫及化疗的ORR达82.2%、DCR为100.0%，中位PFS尚未达到，3~4级不良反应发生率为66%，未发生5级不良反应。SKYSCRAPER-08研究[26]为TIGIT单抗Tiragolumab联合阿替利珠单抗联合化疗一线治疗ESCC疗效和安全性研究，结果显示，Tiragolumab+阿替利珠单抗组和安慰剂组的中位总生存期（Overall survival, OS）分别为15.7个月和11.1个月（HR=0.70，95%CI: 0.55~0.88，P=0.0024）。两组的中位PFS分别为6.2个月和5.4个月（HR=0.56，95%CI: 0.45~0.70，P<0.0001）。总体安全性方面，两组均有98.2%的患者发生任何级别的治疗相关不良事件（Treatment-related adverse events, TRAE）。两组分别有59.6%和56.4%的患者发生3~4级TRAE，分别有2.6%和0.9%发生5级TRAE。除上述研究外，还有免疫联合化疗联合TIGIT的AdvanTIG-105研究[27]、联合FGFR抑制剂[28]及联合EGFR抑制剂[29]小样本Ⅰ~Ⅱ期研究，均显示出初步的抗肿瘤活性。尽管上述研究显示，在免疫治疗联合化疗标准一线方案基础上联合其他类型药物的“加法”方案显示出一定的疗效和安全性，但样本量均较少，且OS结果还未报道。期待更大样本的Ⅲ期临床研究探索这种治疗模式在晚期ESCC一线治疗的OS能否优于免疫联合化疗标准治疗方案。
二是鉴于某些患者不适合化疗联合免疫治疗，采用单纯化疗或免疫治疗无法获得更好的疗效，因此采用免疫联合抗血管生成治疗、化疗联合抗血管生成治疗或双免疫治疗等作为晚期ESCC一线治疗方案。最新的研究进展如下，ALTER-E003研究[30]是探索安罗替尼联合贝莫苏拜单抗（TQB2450, PD-L1抑制剂）一线治疗晚期ESCC的疗效和安全性的Ⅱ期研究，结果显示，安罗替尼联合贝莫苏拜单抗一线治疗晚期ESCC的ORR为69.6%，DCR为91.3%，mPFS达15.44个月，TRAE的发生率为93%（43/46），3级及以上TRAE仅为26%（12/46）。ALTER-E002研究[31]是探索安罗替尼联合紫杉醇+顺铂一线治疗晚期ESCC的疗效和安全性的Ⅱ期研究，结果显示安罗替尼联合紫杉醇+顺铂一线治疗晚期ESCC的ORR为76.1%，mPFS为8.38个月，mOS为18.53个月，且不良反应多为1~2级，因此，该方案在2022版CSCO《食管癌诊疗指南》中入选了一线治疗Ⅲ级推荐（3A类）。CheckMate 648[16]旨在评估纳武利尤单抗联合化疗或双免疫检查点抑制剂（纳武利尤单抗+伊匹单抗）联合治疗一线治疗晚期ESCC的有效性及安全性的Ⅲ期临床试验，结果显示，在总体人群中，双免治疗组中位OS为12.8个月，化疗组为10.7个月（HR=0.78, 98.2%CI: 0.62~0.98, P=0.011）。两组中位缓解持续时间（Duration of response, DoR）分别为11.1月和7.1月。在PD-L1≥1%患者中，双免治疗组的OS 也显著长于单纯化疗组化疗（13.7 vs. 9.1个月；HR=0.64，98.6%CI: 0.46~0.90；P=0.001）。两组中位DoR分别是11.8个月和5.7个月，两组3级或4级TRAE发生率为32%和36%，任何级别TRAE发生率为32%和16%。
4 免疫治疗在晚期食管鳞癌二线及后线治疗的研究进展
免疫治疗在晚期ESCC探索始于二线及后线治疗研究，目前根据KEYNOTE-181[32]、ATTRACTION-3[33]、ESCORT[34]及RATIONALE 302[35]等研究的结果，帕博利珠单抗、纳武利尤单抗、卡瑞利珠单抗、替雷利珠单抗单药治疗被国内CSCO指南纳入晚期ESCC二线治疗Ⅰ级1A类推荐，见表2。
表 2 晚期ESCC的二线免疫治疗的Ⅲ期临床研究Table 2 Phase Ⅲ study of second-line immunotherapy for advanced ESCCTrials Subjects Sample sizes Treatments ORR (%) mPFS (m) mOS (m) ≥Grade 3 adverse
reactions (%)Keynote-181
(China)ESCC 62 vs. 61 Pembrolizumab
vs. chemo (ptx/ doc/
CPT-11)/ 2.5 vs. 2.8
HR=0.84
95%CI:
(0.58–1.23)8.4 vs. 5.6
HR=0.55
95%CI:
(0.36–0.82)21.0 vs. 42.4 Keynote-181
(PD-L1 CPS≥10)ESCC/EAC 107 vs. 115 Pembrolizumab
vs. chemo (ptx/ doc/
CPT-11)21.5 vs. 6.1 2.6 vs. 3.0
HR=0.73
95%CI:
(0.54–0.97)9.3 vs. 6.7
HR=0.69
95%CI:
(0.52–0.93)18.0 vs. 40.9 Attraction-3 ESCC 210 vs. 209 Nivolumab
vs. chemo (ptx/ doc)19.3 vs. 21.5 1.7 vs. 3.4
HR =1.07
95%CI:
(0.87–1.33)10.9 vs. 8.5
HR=0.79
95%CI:
(0.64–0.97)19.1 vs. 63.9 ESCORT ESCC 228 vs. 220 Camrelizumab
vs. chemo (doc/
CPT-11)20.2 vs. 6.4 1.9 vs. 1.9
HR=0.69
95%CI:
(0.56–0.86)8.3 vs. 6.2
HR=0.71
95%CI:
(0.57–0.87)19.0 vs. 40.0 RATIONALE-302 ESCC 256 vs. 256 Tislelizumab
vs. chemo (ptx/ doc/
CPT-11)20.3 vs. 9.8 1.6 vs. 2.1
HR=0.83
95%CI:
(0.67–1.01)8.6 vs. 6.3
HR=0.70
95%CI:
(0.57–0.85)18.8 vs. 55.8 Notes: EAC: esophageal adenocarcinoma; PD-L1: programmed cell death ligand 1; CPS: combined positive score; doc: docetaxel; CPT-11: irinotecan; /: not available. 鉴于食管癌免疫治疗获得性耐药比例约为50%[36]，耐药后的治疗策略目前尚无标准指南推荐。因此二线治疗后新的治疗药物及治疗模式的探索非常关键。CAP02研究[37]旨在评估卡瑞利珠单抗联合阿帕替尼（“双艾”方案）作为ESCC二线治疗的疗效和安全性。结果显示一线免疫治疗失败食管癌患者接受“双艾”方案治疗后ORR达41%，提示“双艾”协同增效，可作为免疫耐药后再挑战的选择。ALTER-E-006研究[38]是一项针对既往经过PD-1/PD-L1/CTLA-4药物（单药或联合）治疗，但未经过抗血管药物治疗的晚期ESCC患者的多中心、回顾性的真实世界研究，用安罗替尼联合免疫检查点抑制剂（不限制产品）进行免疫再挑战治疗，结果显示ORR为29.6%，DCR为91.5%，mPFS为6.31个月，mOS达到10.97个月。AdvanTIG-203研究[39]是一项TIGIT抑制剂Ociperlimab联合替雷利珠单抗（实验组）对比安慰剂联合替雷利珠单抗（对照组）治疗PD-L1 TAP≥10%的一线化疗进展后的晚期ESCC患者的Ⅱ期研究，结果显示实验组的ORR为30.6%，而对照组为20.6%，差异无统计学意义（P=0.2114），两组PFS结果接近（3.4个月vs. 3.5个月，HR=0.93，95%CI: 0.61~1.43）。在一项评估HLX07（抗EGFR单抗）单一疗法或联合疗法作为一线或后线治疗局部晚期、不可切除或转移性ESCC的疗效的Ⅱ期研究中[29]，一线治疗联合组共有30例，用药方案包括HLX07联合斯鲁利单抗和化疗；二线治疗单药组共有19例，用药方案为HLX07单药。结果显示，一线联合组和二线单药组ORR分别为55.2%和23.1%；两组中位PFS分别为未达到和1.5个月。因此，对于晚期ESCC患者，HLX07有一定的疗效。
5 免疫治疗的不良反应及预防策略的进展
免疫治疗的安全性在食管鳞癌治疗过程中非常重要。最近的一项荟萃分析报道了食管癌免疫治疗的TRAEs[40]，与化疗组相比，免疫治疗组的严重TRAEs发生率相对较高（22.66% vs. 11.46%，P=0.059），显著增加了所有级别TRAEs（44.6% vs. 11.09%，P<0.001）和3~5级的免疫相关TRAEs（7.35% vs. 2.25%，P<0.001）发生率。免疫治疗常见不良反应有皮肤、胃肠道、肝脏、内分泌毒性及肺炎等，罕见有神经、眼、心脏毒性等。在大多数研究中，免疫治疗的安全性是可控的，但也有研究报道了严重的心肌炎、肺炎等危及患者生命。因此对于合并自身免疫系统疾病、肝炎、高龄等特殊人群免疫治疗，需要充分评估免疫治疗的耐受性及预期的获益[41]。针对出现的免疫毒性，需评估毒性级别，给予相应处理，并结合恢复情况决定是否再次启动免疫治疗。目前尚无有效的免疫治疗不良反应相关预测生物标志物，需积极探索并寻找更有效的方法进行监测和管理，防止出现严重不良反应。
6 讨论及展望
近年来，免疫治疗全面布局ESCC领域，从二线到一线，从单药到联合，彻底改变了晚期ESCC的治疗格局。然而各种挑战仍然存在：首先，需要寻找新的综合治疗模式，筛选治疗优势人群。免疫联合化疗作为晚期ESCC一线标准治疗，但仍不能满足目前治疗需要。为更好改善预后，在化免基础上探索了联合VEGF-TKI、FGFR抑制剂、 TIGIT单抗及EGFR抑制剂等“加法”研究。同时探索了双免、免疫联合抗血管及化疗联合抗血管治疗的“减法”研究。尽管上述研究部分PFS或ORR获益，但是仍未观察到OS获益，因此需要在早期研究基础上开展探索优势人群综合治疗模式的研究；其次，寻找精准免疫标志物，探索免疫耐药机制，为免疫联合治疗方案提供理论基础。总之，未来还需要开展更多以免疫治疗为基础的相关临床研究来解决上述问题，为晚期ESCC患者带来更大的生存获益。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：段晓阳：文献收集、整理及论文撰写史 健：论文构思、指导及修改 -
表 1 晚期ESCC一线免疫治疗的Ⅲ期研究
Table 1 Phase Ⅲ study of first-line immunotherapy for advanced ESCC
Trials Sample
sizesTreatments ORR(%) mPFS(m) mOS(m) ≥Grade 3 adverse
reactions (%)Keynote-590
(All groups)373/376 Pembrolizumab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)45.0 vs. 29.3 6.3 vs. 5.8
HR=0.65
95%CI:
(0.55–0.76)12.4 vs. 9.8
HR=0.73
95%CI:
(0.62–0.86)71.9 vs. 67.6 Keynote-590
(China)51/55 Pembrolizumab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)37.3 vs. 20.0 6.2 vs. 4.6
HR=0.60
95%CI:
(0.39–0.92)10.5 vs. 8.0
HR=0.51
95%CI:
(0.32–0.81)74.5 vs. 66.7 Checkmate-648 321/324 Nivolumab+
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)47.0 vs. 27.0 5.8 vs. 5.6
HR=0.83
95%CI:
(0.68–1.00)12.8 vs. 10.7
HR=0.78
95%CI:
(0.65–0.93)49.0 vs. 36.0 RATIONALE-306 326/323 Tislelizumab +
chemo (ptx + cis/cis + 5-Fu)
vs. chemo (ptx + cis/cis + 5-Fu)63.5 vs. 42.4 7.3 vs. 5.6
HR=0.62
95%CI:
(0.52–0.75)17.2 vs. 10.6
HR=0.66
95%CI:
(0.54–0.80)67.0 vs. 64.0 ESCORT-1st 298/297 Camrelizumab +
chemo (ptx + cis)
vs. chemo (ptx + cis)72.1 vs. 62.1 6.9 vs. 5.6
HR=0.56
95%CI:
(0.46–0.68)15.3 vs. 12
HR=0.70
95%CI:
(0.56–0.88)63.4 vs. 67.7 ORIENT-15 327/332 Sintilimab + chemo (ptx +
cis / 5-FU + cis)vs.
chemo (ptx + cis/5-FU + cis)66.1 vs. 45.5 7.2 vs. 5.7
HR=0.56
95%CI:
(0.46–0.68)17.4 vs. 12.8
HR=0.66
95%CI:
(0.55–0.79)59.9 vs. 54.5 JUPITER-06 257/257 Toripalimab +
chemo (ptx + cis)
vs. chemo (ptx + cis)69.3 vs. 52.1 5.7 vs. 5.5
HR=0.58
95%CI:
(0.46–0.74)17 vs. 11
HR=0.58
95%CI:
(0.43–0.78)64.6 vs. 56.0 ASTRUM-007 368/183 Serplulimab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)57.6 vs. 42.1 5.8 vs. 5.3
HR=0.60
95%CI:
(0.48–0.75)15.3 vs. 11.8
HR=0.68
95%CI:
(0.53–0.87)64.0 vs. 59.0 GEMSTONE-304 358/182 Sugemalimab +
chemo (cis + 5-Fu)
vs. chemo (cis + 5-Fu)60.1 vs. 45.2 6.2 vs. 5.4
HR=0.67
95%CI:
(0.54–0.82)15.3 vs. 11.5
HR=0.70
95%CI:
(0.55–0.90)51.3 vs. 48.4 Notes: ESCC: esophageal squamous cell carcinoma; Chemo: chemotherapy; cis: cisplatin; 5-FU: 5-Fluorouracil; ptx: paclitaxel; ORR: objective response rate; mPFS: median progression-free survival; mOS: median overall survival; HR: hazard ratio. 
下载: 导出CSV
表 2 晚期ESCC的二线免疫治疗的Ⅲ期临床研究
Table 2 Phase Ⅲ study of second-line immunotherapy for advanced ESCC
Trials Subjects Sample sizes Treatments ORR (%) mPFS (m) mOS (m) ≥Grade 3 adverse
reactions (%)Keynote-181
(China)ESCC 62 vs. 61 Pembrolizumab
vs. chemo (ptx/ doc/
CPT-11)/ 2.5 vs. 2.8
HR=0.84
95%CI:
(0.58–1.23)8.4 vs. 5.6
HR=0.55
95%CI:
(0.36–0.82)21.0 vs. 42.4 Keynote-181
(PD-L1 CPS≥10)ESCC/EAC 107 vs. 115 Pembrolizumab
vs. chemo (ptx/ doc/
CPT-11)21.5 vs. 6.1 2.6 vs. 3.0
HR=0.73
95%CI:
(0.54–0.97)9.3 vs. 6.7
HR=0.69
95%CI:
(0.52–0.93)18.0 vs. 40.9 Attraction-3 ESCC 210 vs. 209 Nivolumab
vs. chemo (ptx/ doc)19.3 vs. 21.5 1.7 vs. 3.4
HR =1.07
95%CI:
(0.87–1.33)10.9 vs. 8.5
HR=0.79
95%CI:
(0.64–0.97)19.1 vs. 63.9 ESCORT ESCC 228 vs. 220 Camrelizumab
vs. chemo (doc/
CPT-11)20.2 vs. 6.4 1.9 vs. 1.9
HR=0.69
95%CI:
(0.56–0.86)8.3 vs. 6.2
HR=0.71
95%CI:
(0.57–0.87)19.0 vs. 40.0 RATIONALE-302 ESCC 256 vs. 256 Tislelizumab
vs. chemo (ptx/ doc/
CPT-11)20.3 vs. 9.8 1.6 vs. 2.1
HR=0.83
95%CI:
(0.67–1.01)8.6 vs. 6.3
HR=0.70
95%CI:
(0.57–0.85)18.8 vs. 55.8 Notes: EAC: esophageal adenocarcinoma; PD-L1: programmed cell death ligand 1; CPS: combined positive score; doc: docetaxel; CPT-11: irinotecan; /: not available.
下载: 导出CSV
-
[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. doi: 10.3322/caac.21834
[2] 谷变利, 马丽霞, 石林林, 等. 食管癌流行病学研究现状及展望[J]. 食管疾病, 2024, 6(2): 148-151. [Gu BL, Ma LX, Shi LL, et al. Advances and Prospects in Epidemiological Research on Esophageal Cancer[J]. Shi Guan Ji Bing, 2024, 6(2): 148-151.] Gu BL, Ma LX, Shi LL, et al. Advances and Prospects in Epidemiological Research on Esophageal Cancer[J]. Shi Guan Ji Bing, 2024, 6(2): 148-151.
[3] 陈万青, 张思维, 陈志峰. 中国食管癌胃癌高发区贲门癌流行趋势分析[J]. 中国肿瘤, 2008, 17(12): 998-1000. [Chen WQ, Zhang SW, Chen ZF. An epidemiologic trend analysis on cardiac cancer in high incidence areas of esophageal cancer and gastric cancer in China[J]. Zhongguo Zhong Liu, 2008, 17(12): 998-1000.] Chen WQ, Zhang SW, Chen ZF. An epidemiologic trend analysis on cardiac cancer in high incidence areas of esophageal cancer and gastric cancer in China[J]. Zhongguo Zhong Liu, 2008, 17(12): 998-1000.
[4] 陈瑜, 蔡文科, 罗小迪, 等. 食管癌地域性差异研究进展[J]. 肿瘤防治研究, 2024, 51(6): 488-494. [Chen Y, Cai WK, Luo XD, et al. Progress of Research on Regional Differences in Esophageal Cancer[J]. Zhong Liu Fang Zhi Yan Jiu, 2024, 51(6): 488-494.] doi: 10.3971/j.issn.1000-8578.2024.23.1227 Chen Y, Cai WK, Luo XD, et al. Progress of Research on Regional Differences in Esophageal Cancer[J]. Zhong Liu Fang Zhi Yan Jiu, 2024, 51(6): 488-494. doi: 10.3971/j.issn.1000-8578.2024.23.1227
[5] 单保恩, 贺宇彤. 2023河北省肿瘤登记年报[M]. 北京: 清华大学出版社, 2023. [Shan BN, He YT. 2023 Hebei Cancer Registry Annual Report[M]. Beijing: Tsinghua University Press, 2023.] Shan BN, He YT. 2023 Hebei Cancer Registry Annual Report[M]. Beijing: Tsinghua University Press, 2023.
[6] 李道娟, 刘言玉, 贺宇彤, 等. 2018年河北省肿瘤登记地区上消化道癌流行现状及1988-2018年高发区流行特征变化趋势[J]. 中国肿瘤, 2023, 32(6): 407-413. [Li DJ, Liu YY, He YT, et al. Incidence and Mortality of Upper Gastrointestinal Cancer in Cancer Registration Areas of Hebei Province in 2018 and the Trends in High Risk Areas from 1988 to 2018[J]. Zhongguo Zhong Liu, 2023, 32(6): 407-413.] Li DJ, Liu YY, He YT, et al. Incidence and Mortality of Upper Gastrointestinal Cancer in Cancer Registration Areas of Hebei Province in 2018 and the Trends in High Risk Areas from 1988 to 2018[J]. Zhongguo Zhong Liu, 2023, 32(6): 407-413.
[7] 宋国慧, 李东方. 河北省磁县食管癌早诊早治实践与思考[J]. 中国肿瘤, 2015, 24(1): 39-41. [Song GH, Li DF. Practice of Early Diagnosis and Treatment for Esophageal Cancer in Cixian, Heibei Province[J]. Zhongguo Zhong Liu, 2015, 24(1): 39-41.] doi: 10.11735/j.issn.1004-0242.2015.01.A008 Song GH, Li DF. Practice of Early Diagnosis and Treatment for Esophageal Cancer in Cixian, Heibei Province[J]. Zhongguo Zhong Liu, 2015, 24(1): 39-41. doi: 10.11735/j.issn.1004-0242.2015.01.A008
[8] 刘言玉, 赵连梅, 贺宇彤, 等. 河北省上消化道恶性肿瘤病因研究及预防[J]. 中国肿瘤, 2023, 32(6): 431-435. [Liu YY, Zhao LM, He YT, et al. Etiology and prevention of upper gastrointestinal cancer in Hebei Province[J]. Zhongguo Zhong Liu, 2023, 32(6): 431-435.] Liu YY, Zhao LM, He YT, et al. Etiology and prevention of upper gastrointestinal cancer in Hebei Province[J]. Zhongguo Zhong Liu, 2023, 32(6): 431-435.
[9] Weidenbaum C, Gibson MK. Approach to Localized Squamous Cell Cancer of the Esophagus[J]. Curr Treat Options Oncol, 2022, 23(10): 1370-1387. doi: 10.1007/s11864-022-01003-w
[10] Wang DR, Wu XL, Sun YL. Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response[J]. Signal Transduct Target Ther, 2022, 7(1): 331. doi: 10.1038/s41392-022-01136-2
[11] Tanaka T, Nakamura J, Noshiro H. Promising immunotherapies for esophageal cancer[J]. Expert Opin Biol Ther, 2017, 17(6): 723-733. doi: 10.1080/14712598.2017.1315404
[12] Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer[J]. Am J Cancer Res, 2020, 10(3): 727-742.
[13] De Silva P, Aiello M, Gu-Trantien C, et al. Targeting CTLA-4 in cancer: Is it the ideal companion for PD-1 blockade immunotherapy combinations?[J]. Int J Cancer, 2021, 149(1): 31-41. doi: 10.1002/ijc.33415
[14] 马兹芬, 许维恒, 金煜翔, 等. 食管癌的靶向治疗与免疫治疗研究进展[J]. 药学实践与服务, 2024, 42(6): 231-237. [Ma ZF, Xu WH, Jin YX, et al. Research progress on targeted therapy and immunotherapy for esophageal cancer[J]. Yao Xue Shi Jian Yu Fu Wu, 2024, 42(6): 231-237.] Ma ZF, Xu WH, Jin YX, et al. Research progress on targeted therapy and immunotherapy for esophageal cancer[J]. Yao Xue Shi Jian Yu Fu Wu, 2024, 42(6): 231-237.
[15] Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study[J]. Lancet, 2021, 398(10302): 759-771. doi: 10.1016/S0140-6736(21)01234-4
[16] Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma[J]. N Engl J Med, 2022, 386: 449-462. doi: 10.1056/NEJMoa2111380
[17] Luo H, Lu J, Bai Y, et al. Effect of Camrelizumab vs. Placebo Added to Chemotherapy on Survival and Progression Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial[J]. JAMA, 2021, 326(10): 916-925. doi: 10.1001/jama.2021.12836
[18] Wang ZX, Cui C, Yao J, et al. Toripalimab plus chemotherapy intreatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial [J]. Cancer Cell, 2022, 40(3): 277-288. e3.
[19] Lu Z, Wang J, Shu Y, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial[J]. BMJ, 2022, 377: e068714.
[20] Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2023, 24(5): 483-495. doi: 10.1016/S1470-2045(23)00108-0
[21] Song Y, Zhang B, Xin D, et al. First-line serplulimab or placebo plus chemotherapy in PD-L1 positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial[J]. Nat Med, 2023, 29(2): 473-482. doi: 10.1038/s41591-022-02179-2
[22] Li J, Chen Z, Bai Y, et al. 0-4 GEMSTONE-304: A phase 3 study of sugemalimab plus chemotherapy versus chemotherapy as first-line treatment of patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC)[J]. Ann Oncol, 2023, 34(Suppl 1): S181-S182.
[23] Sun JM, Lin CY, Rojas C, et al. 1534P First-line lenvatinib (len) plus pembrolizumab (pembro) and chemotherapy (chemo) for metastatic esophageal squamous cell carcinoma (mESCC) : Safety run in results from the phase III LEAP-014 study[J]. Ann Oncol, 2023 (Suppl 2), 34: S863.
[24] Xu M, Pu Y, Jiang Y, et al. 1542P Updated results of a phase II clinical trial: Paclitaxel and carboplatin plus PD-1 blockades combined with anlotinib as first-line treatment for advanced oesophageal cancer[J]. Ann Oncol, 2023 (Suppl 2), 34: S866.
[25] Wang JS, Li N, Guo YZ, et al. TQB2450 plus anlotinib combined with paclitaxel and cisplatin as first-line treatment of advanced esophageal squamous cell carcinoma (ESCC): Update results of a single-arm, multicenter phase Ⅱ trial[J]. J Clin Oncol, 2023, 41(Suppl 16): e16034.
[26] Hsu CH. SKYSCRAPER-08: A phase Ⅲ, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (tira) + atezolizumab (atezo) and chemotherapy (CT) in patients (pts) with esophageal squamous cell carcinoma (ESCC)[R]. San Francisco: ASCO GI, 2024.
[27] Sun M, Spigel DR, Lee YJ, et al. 1533P Advantig-105: Phase Ib dose expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (CT) in patients (pts) with metastatic oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC)[J]. Ann Oncol, 2023 (Suppl 2), 34: S862-S863.
[28] Yamamoto S, Muro K, Nishino K, et al. 1532P Phase Ib study of futibatinib plus pembrolizumab in patients with esophageal carcinoma: Updated results of antitumor activity and tolerability results in combination with chemotherapy[J]. Ann Oncol, 2023 (Suppl 2), 34: S861-S862.
[29] Huang J, Liu Y, Wu T, et al. A phase 2 study of HLX07 as monotherapy or combination therapy in patients with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma[J]. J Clin Oncol, 2023, 41(Suppl 16): 4029.
[30] Hong YG, Meng X, Yang X, et al. 1531P Update results of anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC) : A single arm, multicenter, open label phase Ⅱ clinical trial[J]. Ann Oncol, 2023 (Suppl 2), 34: S861.
[31] Li N, Wu T, Hong YG, et al. A multi-center, single-arm, phase Ⅱ study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma[J]. BMC Med, 2022, 20(1): 472. doi: 10.1186/s12916-022-02649-x
[32] Kojima T, Shah MA, Muro K, et al. Randomized Phase Ⅲ KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer[J]. J Clin Oncol, 2020, 38(35): 4138-4148. doi: 10.1200/JCO.20.01888
[33] Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase3 trial[J]. Lancet Oncol, 2019, 20(11): 1506-1517. doi: 10.1016/S1470-2045(19)30626-6
[34] Huang J, Xu J, Chen Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): amulticentre, randomised, open-label, phase 3 study[J]. Lancet Oncol, 2020, 21(6): 832-842. doi: 10.1016/S1470-2045(20)30110-8
[35] Shen L, Kato K, Kim SB, et al. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase Ⅲ Study[J]. J Clin Oncol, 2022, 40(26): 3065-3076. doi: 10.1200/JCO.21.01926
[36] Zhuo N, Liu C, Zhang Q, et al. Characteristics and prognosis of acquired resistance to immune checkpoint inhibitors in gastrointestinal cancer[J]. JAMA Netw Open, 2022, 5(3): e224637. doi: 10.1001/jamanetworkopen.2022.4637
[37] Meng XR, Wang JS, Xia J, et al. Camrelizumab plus apatinib after progression on immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma (CAP 02 Re-challenge) : A single-arm, multicenter, phase Ⅱ trial[J]. J Clin Oncol, 2024, 42(Suppl 3): 364.
[38] Huang J, Liu J, Hong Y, et al. P-162 Preliminary results of the feasibility and tolerability of anlotinib plus PD-1 blockades among patients with previously immunotherapy treated advanced esophageal squamous cell carcinoma (ESCC): A retrospective exploratory study[J]. Ann Oncol, 2023, 34(Suppl 1): S73.
[39] Wang F, Lin CY, Sun JM, et al. 1020MO AdvanTIG-203: Phase Ⅱ randomized, multicenter study of ociperlimab (OCI) + tislelizumab (TIS) in patients (pts) with unresectable, locally advanced, recurrent/metastatic esophageal squamous cell carcinoma (ESCC) and programmed cell death-ligand 1 (PD-L1) positivity[J]. Ann Oncol, 2023, 34(Suppl 2): S621.
[40] Zheng J, Huang B, Xiao L, et al. Treatment-and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials[J]. Front Oncol, 2022, 12: 821626. doi: 10.3389/fonc.2022.821626
[41] 《中国消化道肿瘤免疫治疗不良反应专家共识(2023年版)》编写组. 中国消化道肿瘤免疫治疗不良反应专家共识(2023年版)[J]. 肿瘤综合治疗电子杂志, 2023, 9(2): 26-60. [Writing group of Consensus on immune-related adverse events of gastrointestinal tumor in China (2023 edition). Consensus on immune-related adverse events of gastrointestinal tumor in China (2023 edition)[J]. Zhong Liu Zong He Zhi Liao Dian Zi Za Zhi, 2019, 9(2): 26-60.] Writing group of Consensus on immune-related adverse events of gastrointestinal tumor in China (2023 edition). Consensus on immune-related adverse events of gastrointestinal tumor in China (2023 edition)[J]. Zhong Liu Zong He Zhi Liao Dian Zi Za Zhi, 2019, 9(2): 26-60.
计量
- 文章访问数: 744
- HTML全文浏览量: 2749
- PDF下载量: 141
