晚期胃癌一线免疫治疗的现状与进展

姜志超; 周爱萍

doi:10.12354/j.issn.1000-8179.2023.20221371

晚期胃癌一线免疫治疗的现状与进展

doi: 10.12354/j.issn.1000-8179.2023.20221371

姜志超,
周爱萍^,

国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院内科（北京市100021）

详细信息

作者简介:
姜志超：专业方向为消化道恶性肿瘤的基础及临床研究

通讯作者:
周爱萍　aiping_zhou@yeah.net

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出版历程
- 收稿日期: 2022-09-26
- 录用日期: 2023-01-12
- 修回日期: 2022-11-22

Current status and progress of first-line immunotherapy for advanced gastric cancer

Zhichao Jiang,
Aiping Zhou^,

Department of Internal Medicine, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

More Information

Corresponding author: Aiping Zhou; E-mail: aiping_zhou@yeah.net

摘要

摘要: 晚期胃癌预后较差，传统化疗疗效有限，未能满足患者治疗需求。免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）已改变晚期胃癌治疗格局，其中程序性死亡受体-1（programmed death-1，PD-1）抑制剂联合化疗、PD-1抑制剂联合曲妥珠单抗及化疗已分别成为人表皮生长因子受体2（human epidermal growth factor receptor 2，HER-2）阴性或阳性晚期胃癌一线治疗选择，其他免疫检查点分子抑制剂和癌症疫苗、过继性细胞输注等疗法的研究均在进行中。如何通过生物标志物筛选免疫治疗最佳获益人群，是近期研究热点。除肿瘤突变负荷、程序性死亡配体-1（programmed death-ligand 1，PD-L1）表达、微卫星不稳定性等，新兴标志物如循环肿瘤DNA、肠道微生物组学和细胞因子等均值得关注。本文就晚期胃癌一线免疫治疗的临床研究进展及展望进行综述。
- 胃癌 /
- 免疫检查点抑制剂 /
- 生物标志物
Abstract: Due to the limited efficacy of chemotherapy, the prognosis of patients with advanced gastric cancer remains poor. There is still a need to optimize the treatments to improve the survival of these patients. Immune checkpoint inhibitors (ICIs) have changed the treatment strategies of advanced gastric cancer. Programmed death-1 (PD-1) inhibitor combined with chemotherapy with or without trastuzumab have brought new treatment options for HER2-negative and HER2-positive advanced gastric cancer patients, respectively. There are a series of ongoing studies to evaluate the efficacy of new ICIs, cancer vaccines, and adoptive cell immunotherapies. Moreover, screening the best beneficiaries of immunotherapy through biomarkers has become one of the hot research areas in gastric cancer. Besides tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1) and microsatellite instability, emerging data suggested that circulating tumor DNA, gut microbiome and cytokines might also be the predictive biomarkers relevant to the effect of immunotherapy. In this review, we will summarize the results of the pivotal first-line immunotherapy clinical trials and biomarker exploratory studies in advanced gastric cancer.
- gastric cacner /
- immune checkpoint inhibitors (ICIs) /
- biomarker

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表 1 胃/胃食管结合部癌中正在进行的ICI联合化疗Ⅲ期相关研究

治疗模式	研究名称	治疗方案	入组患者例数（例）	主要研究终点	计划完成时间
PD-1+化疗	KEYNOTE-859 （NCT03675737）	帕博利珠单抗+化疗 vs. 安慰剂+化疗（化疗方案：顺铂联合5-氟尿嘧啶或奥沙利铂联合卡培他滨）	1579	OS	2024年9月
PD-1+化疗	BGB-A317-305 （NCT03777657）	替雷利珠单抗+化疗 vs. 安慰剂+化疗（化疗方案：顺铂联合5-氟尿嘧啶或奥沙利铂联合卡培他滨）	997	OS	2022年8月
PD-L1+化疗	CS1001-303 （NCT03802591）	舒格利单抗+化疗 vs. 安慰剂+化疗（化疗方案：奥沙利铂联合卡培他滨）	479	PD-L1表达≥5%人群的OS、PFS	2022年4月
PD-1+化疗序贯PD-1+靶向	SHR-1210-Ⅲ-311 （NCT03813784）	卡瑞利珠单抗+化疗序贯卡瑞利珠单抗+阿帕替尼 vs. 卡瑞利珠单抗+化疗序贯阿帕替尼 vs. 化疗（化疗方案：奥沙利铂联合卡培他滨）	887	全人群及PD-L1表达阳性人群的OS	2022年2月

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表 3 目前G/GEJ癌中正在进行的新型免疫双抗相关研究

靶点	药物名称	研究名称（分期）	研究人群	主要终点及初步数据
PD-1×CTLA-4	AK104	NCT03852251（Ⅰb/Ⅱ期）	实体瘤/晚期或转移性GEJ癌	ORR：66.7%；DCR：95.8%；6个月PFS：69.5%
PD-1×CTLA-4	AK104	NCT05008783（Ⅲ期）局部晚期不可切除或转移性胃腺癌/GEJ腺癌	PFS、OS	-
PD-1×PD-L1	IBI318	NCT03875157（Ⅰ期）	晚期实体瘤（包括胃癌）	DLT、AE及治疗反应；TRAE11/14例
PD-1×4-1BB	ES101	NCT04009460（Ⅰ期）	晚期实体瘤（包括胃癌）	MTD、AE
PD-1×CD47	HX009	NCT04097769（Ⅰ期）	晚期实体瘤（包括胃癌）	DLT、AE
PD-1×CD47	IBI322	NCT04912466（Ⅰ期）	晚期实体瘤（包括胃癌）	DLT、AE及缓解率
PD-1×LAG-3	MGD013	NCT03219268（Ⅰ期）	晚期肝癌/胃癌/GEJ癌	MTD、AE；≥3级TRAE23.3%
AE：不良事件；DLT：剂量限制毒性；Lag-3：淋巴细胞活化基因3；MTD：最大耐受剂量；TRAE：治疗相关不良事件

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表 2 胃/食管/GEJ癌中已完成的ICI联合化疗的大型Ⅲ期临床研究结果汇总

研究	CPS （分）	治疗臂	主要终点	ORR（%）	中位PFS（月）	HR（95%CI）	中位OS（月）	HR（95%CI）
Checkmate-649^[11,14]	≥5	纳武利尤单抗+化疗	PD-L1 CPS≥5分人群的OS和PFS	60.0	8.1（7.0～9.2）	0.70（0.60～0.81）	14.4（13.1～16.2）	0.70（0.61～0.81）
	≥5	化疗		45.0	6.1（5.6～6.9）	0.70（0.60～0.81）	11.1（10.2～12.1）	0.70（0.61～0.81）
	全人群	纳武利尤单抗+化疗		58.0	7.7（7.1～8.6）	0.79（0.70～0.89）	13.8（12.4～14.5）	0.79（0.71～0.88）
	全人群	化疗		46.0	6.9（6.7～7.2）	0.79（0.70～0.89）	11.6（10.9～12.5）	0.79（0.71～0.88）
	≥5	纳武利尤单抗+伊匹木单抗		27.0	2.8（2.6～4.0）	1.42（1.14～1.76）	11.2（9.2～13.4）	0.89（0.71～1.10）
	≥5	化疗		47.0	6.3（5.6～7.1）	1.42（1.14～1.76）	11.6（10.1～12.7）	0.89（0.71～1.10）
	全人群	纳武利尤单抗+伊匹木单抗		23.0	2.8（2.6～3.6）	1.66（1.40～1.95）	11.7（9.6～13.5）	0.91（0.77～1.07）
	全人群	化疗		47.0	7.1（6.9～8.2）	1.66（1.40～1.95）	11.8（11.0～12.7）	0.91（0.77～1.07）
ATTRACTION-04^[15]	-	纳武利尤单抗+化疗	PFS和OS（任意阳性即可）	57.0	10.5（8.4～14.8）	0.68（0.51～0·90）	17.45（15.67～20.83）	0.90（0.75～1.08）
ATTRACTION-04^[15]	-	化疗	PFS和OS（任意阳性即可）	48.0	8.3（7.0～9.4）	0.68（0.51～0·90）	17.15（15.18～19.65）	0.90（0.75～1.08）
ORIENT-16^[17]	≥5	信迪利单抗+化疗	PD-L1 CPS≥5分和全人群的OS	72.8	7.7（6.9～9.7）	0.63（0.49～0.81）	18.4（14.6～NC）	0.66（0.51～0.86）
	≥5	化疗		59.6	5.8（5.5～6.9）	0.63（0.49～0.81）	12.9（11.1～15.4）	0.66（0.51～0.86）
	全人群	信迪利单抗+化疗		58.2	7.1（6.9～8.5）	0.63（0.53～0.77）	15.2（12.9～18.4）	0.77（0.63～0.93）
	全人群	化疗		48.4	5.7（5.5～6.9）	0.63（0.53～0.77）	12.3（11.3～13.8）	0.77（0.63～0.93）
KEYNOTE-062^[7,16]	≥1	帕博利珠单抗+化疗	免疫联合化疗组对比化疗组的优效性：PD-L1 CPS≥1分、 ≥10分人群的OS及PD-L1 CPS≥1分人群的PFS	49.0	6.9（5.8～7.8）	0.84（0.70～1.01）	12.5（10.8～13.9）	0.85（0.71～1.02）
		化疗	免疫联合化疗组对比化疗组的优效性：PD-L1 CPS≥1分、 ≥10分人群的OS及PD-L1 CPS≥1分人群的PFS	37.0	6.5（5.7～7.1）	0.84（0.70～1.01）	11.1（9.2～12.8）	0.85（0.71～1.02）
		帕博利珠单抗	免疫单药组组对比化疗组的非劣效：PD-L1 CPS≥1分人群的OS	15.0	2.0（1.5～2.8）	1.66（1.37～2.01）	10.6（7.7～13.8）	0.90（0.75～1.08）
		化疗	免疫单药组组对比化疗组的非劣效：PD-L1 CPS≥1分人群的OS	37.0	6.4（5.7～7.0）	1.66（1.37～2.01）	11.1（9.2～12.8）	0.90（0.75～1.08）

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