晚期结直肠癌三线免疫联合方案与单药化疗或单药靶向治疗的疗效对比Meta分析

doi:10.3877/cma.j.issn.2095-3224.2026.03.004

目的

系统评价晚期结直肠癌（mCRC）三线治疗中免疫联合方案与单药化疗或单药靶向治疗的疗效与安全性差异，为后线策略选择提供循证依据。

方法

按照PRISMA 2020报告规范构建PICO框架，系统检索PubMed、Embase、Cochrane Library、Web of Science、Scopus、CNKI、万方、维普和SinoMed，检索时限为建库至2025年12月31日。纳入比较免疫联合方案（T组）与单药化疗或单药靶向治疗或可分层常规后线对照方案（C组）的随机对照研究、前瞻性研究或对照队列研究。提取客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）及不良反应发生率。采用RevMan 5.4及固定效应模型进行Meta分析，二分类结局以风险比（RR）及95%CI表示，异质性采用Cochran’s Q检验与I²评价，并进行敏感性分析和发表偏倚评价。

结果

联合模式以抗血管生成小分子（瑞戈非尼、呋喹替尼、阿帕替尼等）联合PD-1抑制剂为主。T组ORR显著高于C组[OR=3.55，95%CI：2.38~5.29，P＜0.001]；DCR亦显著升高[OR=2.20，95%CI：1.49~3.26，P=0.001]。T组与C组在PFS上差异具有统计学意义[OR=1.35，95%CI：1.08~1.68，P=0.008]；OS亦明显改善[OR=2.08，95%CI：1.44~2.99，P=0.001]。安全性方面总体不良反应发生率差异无统计学意义[OR=1.18，95%CI：0.94~1.47，P=0.150]。各结局异质性均较低（I²≈0%）。

结论

免疫联合方案治疗mCRC三线及以后患者疗效优于单药化疗或单药靶向治疗，可显著提高ORR、DCR，延长PFS、OS，且安全性相当，可为临床后线治疗提供参考。

关键词: 结直肠癌, 晚期结直肠癌, 三线治疗, 免疫联合, 瑞戈非尼, 呋喹替尼, Meta分析

Objective

To systematically evaluate the efficacy and safety differences between immune combination regimens and single-agent chemotherapy/single-agent targeted therapy in the third-line treatment of metastatic colorectal cancer (mCRC), providing an evidence-based basis for the selection of later-line strategies.

Methods

This systematic review was conducted according to the PRISMA 2020 statement and a predefined PICO framework. PubMed, Embase, Cochrane Library, Web of Science, Scopus, CNKI, Wanfang, VIP and SinoMed were searched from inception to December 31, 2025. Randomized trials, prospective studies and controlled cohort studies comparing immune combination regimens (group T) with single-agent chemotherapy/targeted therapy or stratifiable conventional later-line control regimens (group C) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were extracted. RevMan 5.4 was used for Meta-analysis. Dichotomous outcomes were pooled as risk ratios (RR) with 95%CI. Heterogeneity was assessed using Cochran’s Q test and I² statistics, and sensitivity analyses and publication-bias assessments were performed.

Results

The included studies were published between 2021 and 2025, with the combination mode primarily consisting of anti-angiogenic small molecules (regorafenib, fruquintinib, apatinib, etc.) combined with PD-1 inhibitors. ORR (582 cases in Group T and 543 cases in Group C) showed that the combined regimen significantly improved the objective response rate [OR=3.55, 95%CI: 2.38~5.29, P＜0.001]. DCR (504 cases in Group T and 465 cases in Group C) also significantly increased [OR=2.20, 95% CI: 1.49~3.26, P=0.001]. PFS (850 cases in Group T and 1 022 cases in Group C) demonstrated a statistical advantage for the combined regimen [OR=1.35, 95% CI: 1.08~1.68, P=0.008]. OS (836 cases in Group T and 1 008 cases in Group C) also significantly improved [OR=2.08, 95% CI: 1.44~2.99, P=0.001]. In terms of safety (770 cases in Group T and 941 cases in Group C), there was no statistically significant difference in the overall incidence of adverse reactions [OR=1.18, 95% CI: 0.94~1.47, P=0.150]. The heterogeneity for each outcome was low (I²≈0%).

Conclusion

The efficacy of immunotherapy combined regimen in the treatment of mCRC patients as a third-line therapy is superior to that of monotherapy chemotherapy/targeted therapy, significantly improving ORR and DCR, prolonging PFS and OS, and maintaining comparable safety. This provides a reference for clinical later-line treatment.

Key words: Colorectal cancer, Advanced colorectal cancer, Third-line treatment, Immune combination, Regorafenib, Fruquintinib, Meta-analysis

图1 文献筛选流程图

表1 纳入文献的基本资料

第一作者	发表年份	样本量（例）		性别（男/女）		年龄（岁）		干预措施		结局指标
第一作者	发表年份	T组	C组	T组	C组	T组	C组	T组	C组	结局指标
Wang F^［6］	2021	22	20	12/10	10/10	53.23±3.69	54.39±3.89	瑞戈非尼+特瑞普利单抗（PD-1）	瑞戈非尼单药	ORR、DCR、PFS、OS、不良反应率
Yu W^［7］	2021	33	30	15/18	15/15	53.64±5.34	53.12±4.22	瑞戈非尼+特瑞普利单抗（PD-1）	瑞戈非尼	ORR、DCR、PFS、OS、不良反应率
Sun L^［8］	2021	28	23	13/15	14/9	54.6±11.7	53.0±12.02	呋喹替尼+PD-1抑制剂	瑞戈非尼单药	ORR、DCR、PFS、OS、不良反应率
Li RR^［9］	2022	103	100	56/47	50/50	56.22±5.63	57.02±6.02	瑞戈非尼+抗PD-1抗体（多种）	瑞戈非尼单药	OS、PFS、ORR、DCR、不良反应率
Gou M^［10］	2022	45	42	30/15	25/15	54.10±4.36	54.69±5.23	呋喹替尼+PD-1抑制剂	呋喹替尼	ORR、DCR、PFS、OS、不良反应率
Fakih M^［11］	2022	42	30	23/19	13/17	59.22±5.98	58.96±7.02	瑞戈非尼+信迪利单抗	呋喹替尼+信迪利单抗	PFS、ORR、DCR、OS、不良反应率
Yang X^［12］	2023	70	68	37/33	34/34	60.58±3.99	61.22±5.23	呋喹替尼+PD-1抑制剂	呋喹替尼	ORR、DCR、PFS、OS、不良反应率
Qu W^［13］	2024	161	376	102/59	264/112	59.69±4.88	60.52±4.98	瑞戈非尼+免疫检查点抑制剂	瑞戈非尼单药	OS、PFS、不良反应率
Wang RT^［14］	2021	110	96	55/55	59/37	55.96±6.98	56.78±5.78	瑞戈非尼单药+PD-1	瑞戈非尼单药	ORR、DCR、PFS、OS、不良反应率
Kim DW^［15］	2024	51	56	27/24	28/28	56.22±6.02	57.60±8.02	瑞戈非尼+纳武利尤单抗（PD-1）	瑞戈非尼单药	ORR、DCR、PFS、OS
李建平^［16］	2025	33	33	19/14	20/13	62.88±7.29	63.72±7.45	FOLFOXIRI方案+贝伐珠单抗	FOLFOXIRI方案	ORR、PFS、OS、不良反应率
袁世发^［17］	2025	45	45	26/19	25/20	45.80±4.45	45.86±4.56	雷替曲塞+奥沙利铂+贝伐珠单抗	雷替曲塞+奥沙利铂	ORR、PFS、OS、不良反应率
李凡^［18］	2025	32	32	19/13	21/11	53.36±6.35	51.99±6.87	阿帕替尼+卡瑞利珠单抗	阿帕替尼单药	PFS、OS、不良反应发生率
李阳^［19］	2025	46	46	26/20	28/18	57.89±7.86	58.38±8.41	信迪利单抗+瑞戈非尼	瑞戈非尼	PFS、OS、不良反应率
于瀚卿^［20］	2025	29	25	20/9	12/13	62.02±5.02	61.89±5.48	瑞戈非尼+免疫治疗	瑞戈非尼单药	PFS、OS

表1 纳入文献的基本资料

第一作者	发表年份	样本量（例）		性别（男/女）		年龄（岁）		干预措施		结局指标
第一作者	发表年份	T组	C组	T组	C组	T组	C组	T组	C组	结局指标
Wang F^［6］	2021	22	20	12/10	10/10	53.23±3.69	54.39±3.89	瑞戈非尼+特瑞普利单抗（PD-1）	瑞戈非尼单药	ORR、DCR、PFS、OS、不良反应率
Yu W^［7］	2021	33	30	15/18	15/15	53.64±5.34	53.12±4.22	瑞戈非尼+特瑞普利单抗（PD-1）	瑞戈非尼	ORR、DCR、PFS、OS、不良反应率
Sun L^［8］	2021	28	23	13/15	14/9	54.6±11.7	53.0±12.02	呋喹替尼+PD-1抑制剂	瑞戈非尼单药	ORR、DCR、PFS、OS、不良反应率
Li RR^［9］	2022	103	100	56/47	50/50	56.22±5.63	57.02±6.02	瑞戈非尼+抗PD-1抗体（多种）	瑞戈非尼单药	OS、PFS、ORR、DCR、不良反应率
Gou M^［10］	2022	45	42	30/15	25/15	54.10±4.36	54.69±5.23	呋喹替尼+PD-1抑制剂	呋喹替尼	ORR、DCR、PFS、OS、不良反应率
Fakih M^［11］	2022	42	30	23/19	13/17	59.22±5.98	58.96±7.02	瑞戈非尼+信迪利单抗	呋喹替尼+信迪利单抗	PFS、ORR、DCR、OS、不良反应率
Yang X^［12］	2023	70	68	37/33	34/34	60.58±3.99	61.22±5.23	呋喹替尼+PD-1抑制剂	呋喹替尼	ORR、DCR、PFS、OS、不良反应率
Qu W^［13］	2024	161	376	102/59	264/112	59.69±4.88	60.52±4.98	瑞戈非尼+免疫检查点抑制剂	瑞戈非尼单药	OS、PFS、不良反应率
Wang RT^［14］	2021	110	96	55/55	59/37	55.96±6.98	56.78±5.78	瑞戈非尼单药+PD-1	瑞戈非尼单药	ORR、DCR、PFS、OS、不良反应率
Kim DW^［15］	2024	51	56	27/24	28/28	56.22±6.02	57.60±8.02	瑞戈非尼+纳武利尤单抗（PD-1）	瑞戈非尼单药	ORR、DCR、PFS、OS
李建平^［16］	2025	33	33	19/14	20/13	62.88±7.29	63.72±7.45	FOLFOXIRI方案+贝伐珠单抗	FOLFOXIRI方案	ORR、PFS、OS、不良反应率
袁世发^［17］	2025	45	45	26/19	25/20	45.80±4.45	45.86±4.56	雷替曲塞+奥沙利铂+贝伐珠单抗	雷替曲塞+奥沙利铂	ORR、PFS、OS、不良反应率
李凡^［18］	2025	32	32	19/13	21/11	53.36±6.35	51.99±6.87	阿帕替尼+卡瑞利珠单抗	阿帕替尼单药	PFS、OS、不良反应发生率
李阳^［19］	2025	46	46	26/20	28/18	57.89±7.86	58.38±8.41	信迪利单抗+瑞戈非尼	瑞戈非尼	PFS、OS、不良反应率
于瀚卿^［20］	2025	29	25	20/9	12/13	62.02±5.02	61.89±5.48	瑞戈非尼+免疫治疗	瑞戈非尼单药	PFS、OS

图2 偏倚风险条形图

图3 偏倚风险总图

图4 两组ORR比较

图5 两组DCR比较

图6 两组PFS比较

图7 两组OS比较

图8 两组不良反应发生率比较

图9 漏斗图示意图：显示潜在发表偏倚

[1]	Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040[J]. Transl Oncol, 2021, 14(10): 101174.
[2]	Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up[J]. Ann Oncol, 2023, 34(1): 10-32.
[3]	Ciracì P, Studiale V, Taravella A, et al. Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm[J]. Nat Rev Clin Oncol, 2025, 22(1): 28-45.
[4]	Tu J, Liang H, Li C, et al. The application and research progress of anti-angiogenesis therapy in tumor immunotherapy[J]. Front Immunol, 2023, 14: 1198972.
[5]	Xiao M, Shi Y, Jiang S, et al. Recent advances of nanomaterial-based anti-angiogenic therapy in tumor vascular normalization and immunotherapy[J]. Front Oncol, 2022, 12: 1039378.
[6]	Wang F, He MM, Yao YC, et al. Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/Ⅱ clinical trial and gut microbiome analysis[J]. Cell Rep Med, 2021, 2(9): 100383.
[7]	Yu W, Tao Q, Zhang Y, et al. Efficacy and safety of regorafenib combined with toripalimab in the third-line and beyond treatment of advanced colorectal cancer[J]. J Oncol, 2021, 2021: 9959946.
[8]	Sun L, Huang S, Li D, et al. Efficacy and safety of fruquintinib plus PD-1 inhibitors versus regorafenib plus PD-1 inhibitors in refractory microsatellite stable metastatic colorectal cancer[J]. Front Oncol, 2021, 11: 754881.
[9]	Li RR, Yin XL, Zeng DY, et al. Efficacy and safety of anti-PD-1 antibody plus regorafenib in refractory microsatellite stable metastatic colorectal cancer: a retrospective single-arm cohort study[J]. Ann Transl Med, 2022, 10(16): 880.
[10]	Gou M, Qian N, Zhang Y, et al. Fruquintinib in combination with PD-1 inhibitors in patients with refractory non-MSI-H/pMMR metastatic colorectal cancer: a real-world study in China[J]. Front Oncol, 2022, 12: 851756.
[11]	Fakih M, Raghav KPS, Chang DZ, et al. Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study[J]. E Clinical Medicine, 2023, 58: 101917.
[12]	Yang X, Yin X, Qu X, et al. Efficacy, safety, and predictors of fruquintinib plus anti-programmed death receptor-1 (PD-1) antibody in refractory microsatellite stable metastatic colorectal cancer in a real-world setting: a retrospective cohort study[J]. J Gastrointest Oncol, 2023, 14(6): 2425-2435.
[13]	Qu W, Liu Z, Chen X, et al. Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China[J]. BMC Cancer, 2024, 24(1): 22.
[14]	Wang RT, Zhao Y, Wang AL, et al. Efficacy and safety of regorafenib monotherapy among patients with previously treated metastatic colorectal cancer in a Chinese population: a real-world exploratory study[J]. Int J Gen Med, 2021, 14: 5363-5373.
[15]	Kim DW, Kim YC, Kovari BP, et al. Biomarker analysis from a phase Ⅰ/Ⅰb study of regorafenib and nivolumab in mismatch repair-proficient advanced refractory colorectal cancer[J]. Cancers (Basel), 2024, 16(3): 556.
[16]	李建平, 余世潮, 伍凯丽, 等. FOLFOXIRI方案联合贝伐珠单抗在局部晚期结直肠癌新辅助治疗中的应用效果及安全性[J]. 临床合理用药, 2025, 18(26): 89-91.
[17]	袁世发, 刘彩霞, 刘志军, 等. 贝伐珠单抗、雷替曲塞联合奥沙利铂治疗晚期结直肠癌45例[J]. 安徽医药, 2025, 29(9): 1887-1890.
[18]	李凡, 李晓棠. 阿帕替尼联合卡瑞利珠单抗后线治疗晚期结直肠癌的疗效观察[J]. 中国肛肠病杂志, 2025, 45(7): 21-24.
[19]	李阳, 张晶, 时欣, 等. TAS-102联合信迪利单抗、瑞戈非尼治疗经标准方案治疗失败的晚期结直肠癌的临床观察[J]. 疑难病杂志, 2025, 24(2): 155-159.
[20]	于瀚卿, 范璐璐, 贾振亚, 等. 瑞戈非尼联合免疫治疗或化疗后线治疗转移性结直肠癌的临床研究[J]. 药学进展, 2025, 49(9): 758-763.
[21]	Newport EL, Pedrosa AR, Njegic A, et al. Improved immunotherapy efficacy by vascular modulation[J]. Cancers (Basel), 2021, 13(20): 5207.
[22]	Yu P, Wang Y, Yuan D, et al. Vascular normalization: reshaping the tumor microenvironment and augmenting antitumor immunity for ovarian cancer[J]. Front Immunol, 2023, 14(2): 1276694.
[23]	Ayala-de Miguel C, Jiménez-Castro J, Sánchez-Vegas A, et al. Third-line treatment and beyond in metastatic colorectal cancer: what do we have and what can we expect?[J]. Crit Rev Oncol Hematol, 2024, 202: 104454.
[24]	Gao L, Tang L, Hu Z, et al. Comparison of the efficacy and safety of third-line treatments for metastatic colorectal cancer: a systematic review and network meta-analysis[J]. Front Oncol, 2023, 13: 1269203.
[25]	Hoyek C, Naqvi SAA, Sahvan O, et al. Evaluating third-line therapies in refractory metastatic colorectal cancer: a systematic review and network meta-analysis[J]. Dig Liver Dis, 2025, 57(12): 2297-2303.

[1]	佘欣怡, 万玮祺, 刘广健, 黄玉笑, 胡金枝, 覃斯. 超声造影定量评估结直肠癌化疗后肝窦阻塞综合征的前瞻性临床研究[J/OL]. 中华医学超声杂志（电子版）, 2026, 23(02): 151-161.
[2]	耿富良, 黄坤超, 李宗霖, 田云周. 连续缝合与间断缝合在腹腔镜消化性溃疡穿孔修补术中应用的Meta分析[J/OL]. 中华普通外科学文献(电子版), 2026, 20(02): 138-144.
[3]	刘千什, 刘昶. 影响造口旁疝修补术后复发相关因素的系统评价及Meta分析[J/OL]. 中华疝和腹壁外科杂志(电子版), 2026, 20(02): 221-225.
[4]	王浩, 张伟杰, 员百慧, 宋知远, 于艳龙. 甘油三酯葡萄糖指数预测急性胰腺炎严重程度Meta分析[J/OL]. 中华肝脏外科手术学电子杂志, 2026, 15(03): 405-412.
[5]	王浩, 辛才进, 崔静, 傅鹤鑫, 朱长仁, 汪刘华. 错配修复蛋白在早发性结直肠癌中的表达及意义[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(03): 209-214.
[6]	王利明, 马浩越, 余永刚, 陈瑛罡. 结直肠癌手术切除范围的理论依据[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(02): 115-121.
[7]	张雨霄, 潘怡, 邱田, 邹霜梅. 行二代测序结直肠癌患者cMET的表达水平与临床病理特征和分子特征的相关性及预后价值的研究[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(02): 122-132.
[8]	温钰, 张尊庶, 丁泽浩, 郑仁杰, 武宾, 孙海翔, 韩超, 黄陈. 基于淋巴结转移的结直肠癌新分期与预后关系[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(02): 133-145.
[9]	王欢, 王伟彪, 李多, 于永强, 武雪亮, 樊建春. 基于溶酶体相关基因构建结直肠癌预后模型的研究[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(02): 146-159.
[10]	张钧, 梁宗康, 高天, 闫泽宇, 王刚, 高鹏, 何显力. SEMS植入后序贯新辅助治疗与腹腔镜手术在梗阻性结直肠癌中的应用效果对比：一项倾向评分匹配研究[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(02): 160-167.
[11]	张逸辰, 冯雨舟, 鲍传庆. PROTAC在结直肠癌肿瘤微环境治疗中的研究进展[J/OL]. 中华结直肠疾病电子杂志, 2026, 15(02): 175-180.
[12]	田子颖, 陈文华, 纪任欣. 不同电刺激疗法治疗神经源性膀胱的系统评价及Meta分析[J/OL]. 中华神经创伤外科电子杂志, 2026, 12(02): 98-107.
[13]	张婧萱, 郭佳星, 李紫红, 陈怡颖, 乔媛, 宝莹娜. 多线治疗失败后31例复发转移性结直肠癌局部挽救性放射治疗的研究[J/OL]. 中华消化病与影像杂志(电子版), 2026, 16(03): 206-211.
[14]	梁玮龙, 王鹏飞, 高怀新. 氟比洛芬酯联合腹横肌平面阻滞在腹腔镜结直肠癌根治术中的麻醉效果及对COX-2、MMP-9水平的影响[J/OL]. 中华消化病与影像杂志(电子版), 2026, 16(03): 256-261.
[15]	倪玮峰, 田文扬, 倪雨玲, 杨海宁, 施岳柱. 脂质代谢在七氟烷与丙泊酚麻醉对老年结直肠癌患者认知功能中的作用[J/OL]. 中华消化病与影像杂志(电子版), 2026, 16(02): 173-178.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Meta-analysis of the efficacy of third-line immune combination regimens versus single-agent chemotherapy or single-agent targeted therapy in advanced colorectal cancer

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Meta-analysis of the efficacy of third-line immune combination regimens versus single-agent chemotherapy or single-agent targeted therapy in advanced colorectal cancer