转移性结直肠癌三线治疗的研究现状及进展

刘婧禹; 尹桐; 吴玥; 彭小波; 湛先保

doi:10.19401/j.cnki.1007-3639.2025.11.008

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转移性结直肠癌三线治疗的研究现状及进展

综述 | 更新时间：2025-12-31

- 转移性结直肠癌三线治疗的研究现状及进展
- Research status and progress of third-line treatment for metastatic colorectal cancer
- 中国癌症杂志 2025年35卷第11期页码：1056-1066
- 作者机构：
  
  海军军医大学第一附属医院肿瘤科，上海 200433
- 作者简介：
  
  [ "刘婧禹（ORCID: 0009-0003-4710-2012），博士。" ]
  湛先保（ORCID: 0000-0003-3718-466X），博士，主任医师，肿瘤科科主任，E-mail: zhanxianbao@126.com。
- 基金信息：
  
  海军军医大学基础医学研究基金项目(2023MS023)
- DOI：10.19401/j.cnki.1007-3639.2025.11.008
  中图分类号： R735.3
- 收稿：2025-04-24，
  
  修回：2025-07-14，
  
  纸质出版：2025-11-30
- 稿件说明：
移动端阅览
刘婧禹, 尹桐, 吴玥, 等. 转移性结直肠癌三线治疗的研究现状及进展[J]. 中国癌症杂志, 2025,35(11):1056-1066.

Jingyu LIU, Tong YIN, Yue WU, et al. Research status and progress of third-line treatment for metastatic colorectal cancer[J]. China Oncology, 2025, 35(11): 1056-1066.
刘婧禹, 尹桐, 吴玥, 等. 转移性结直肠癌三线治疗的研究现状及进展[J]. 中国癌症杂志, 2025,35(11):1056-1066. DOI： 10.19401/j.cnki.1007-3639.2025.11.008.

Jingyu LIU, Tong YIN, Yue WU, et al. Research status and progress of third-line treatment for metastatic colorectal cancer[J]. China Oncology, 2025, 35(11): 1056-1066. DOI： 10.19401/j.cnki.1007-3639.2025.11.008.

摘要

转移性结直肠癌（metastatic colorectal cancer，mCRC）的三线治疗指在一线、二线治疗失败或患者无法耐受后采用的后续治疗方案，是临床实践中的关键难题，也是近年来转化医学研究的核心领域。随着分子分型技术的普及和新型疗法的涌现，三线治疗策略正从传统

化疗向精准靶向治疗联合免疫治疗转变。本研究通过检索PubMed、ClinicalTrials.gov数据库及美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）、欧洲肿瘤内科学会（European Society for Medical Oncology，ESMO）的会议摘要，纳入Ⅲ期随机对照试验、Ⅰ/Ⅱ期前沿临床研究及权威综述，重点关注生存获益、耐药性及生物标志物相关数据。全面梳理了近年来mCRC三线治疗领域的重要进展，包括三线标准药物及治疗[瑞戈非尼、呋喹替尼、曲氟尿苷替匹嘧啶、抗表皮生长因子（epidermal growth factor receptor，EGFR）再挑战治疗

]

、靶向治疗（如

BRAF

V600E抑制剂、

ERBB2

扩增、

KRAS

G12C抑制剂）、免疫治疗[微卫星高度不稳定（microsatellite instability-high，MSI-H）/错配修复缺陷（deficient mismatch repair，dMMR）、微卫星稳定（microsatellite stable，MSS）/错配修复完整（proficient mismatch repair，pMMR）及靶免联合治疗

]

的最新临床证据。其中靶向治疗领域取得显著突破：抗EGFR再挑战治疗通过循环肿瘤DNA（circulating tumor DNA，ctDNA）动态监测筛选

RAS

BRAF

野生型患者，使中位总生存期（overall survival，OS）延长至17.3个月，但耐药机制复杂，继发突变率高，需进一步优化动态监测体系；针对

BRAF

V600E突变，三联方案（康奈非尼+比美替尼+西妥昔单抗）较传统治疗中位OS延长至9.3个月[风险比（hazard ratio，HR）=0.52

]

；KRAS G12C抑制剂阿达格拉西布（adagrasib）联合西妥昔单抗的客观缓解率（objective response rate，ORR）提升至34%，中位OS达15.9个月，但肿瘤耐药仍是主要挑战。免疫治疗方面，MSI-H/dMMR患者通过双免疫联合治疗（纳武利尤单抗+伊匹木单抗）获得71%的4年OS率，而MSS型患者依赖免疫-靶向联合治疗策略（如卡博替尼+德瓦鲁单抗），ORR提升至27.6%。新兴治疗领域主要包括人工智能平台的搭建、肠道菌群作为生物标志物与粪便微生物群移植的创新疗法及嵌合抗原受体T（chimeric antigen receptor-T，CAR-T）细胞疗法的最新进展。本综述通过探讨mCRC三线治疗的研究现状及进展，旨在为优化临床决策及未来研究方向提供参考。

Abstract

Third-line treatment for metastatic colorectal cancer (mCRC) refers to subsequent therapeutic interventions following the failure or intolerance of first- and second-line treatments. This represents a critical challenge in clinical practice and a core focus of translational medicine research in recent years. With advancements in molecular typing technologies and the emergence of novel therapies

the third-line treatment strategy has evolved from traditional chemotherapy toward precision targeting and immunotherapy. A comprehensive literature search was conducted across PubMed

ClinicalTrials.gov database and American Society of Clinical Oncology (ASCO)

European Society for Medical Oncology (ESMO) conference abstracts. Phase Ⅲ

randomized controlled trials

phase Ⅰ/Ⅱ frontier clinical studies

and authoritative reviews were included

with an emphasis on data related to survival benefits

drug resistance mechanisms

and biomarkers. This review provided an in-depth analysis of significant progress in third-line treatment strategies for mCRC

encompassing standard therapies [regorafenib

fruquintinib

trifluridine/tipiracil

anti- epidermal growth factor receptor (EGFR) rechallenge therapy

]

targeted therapies (e.g.

BRAF

V600E inhibitors

ERBB2

amplification inhibitors

KRAS

G12C inhibitors) and immunotherapies [microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR)

microsatellite stable (MSS)/proficient mismatch repair (pMMR) and target-immune combination therapies

]

. Notable breakthroughs have been achieved in targeted therapies. Anti-EGFR rechallenge therapy extended the median overall survival (OS) to 17.3 months in RAS/BRAF wild-type patients identified through dynamic circulating tumor DNA (ctDNA) monitoring. However

drug resistance remains complex

with high secondary mutation rates necessitating further optimization of dynamic monitoring systems. For

BRAF

V600E mutations

triple therapy (encorafenib+binimetinib+cetuximab) demonstrated a median OS of 9.3 months [hazard ratio (HR)=0.52

]

surpassing conventional treatments. The combination of KRAS G12C inhibitor adagrasib with cetuximab achieved an objective response rate (ORR) of 34% and a median OS of 15.9 months

though tumor resistance continued to pose challenges. In the realm of immunotherapy

dual immunotherapy (nivolumab+ipilimumab) yielded a 4-year OS rate of 71% in MSI-H/dMMR patients. For MSS patients

immune-targeted combination strategies (e.g.

cabozantinib+atezolizumab) increased the ORR to 27.6%. Emerging therapies include artificial intelligence platforms for precision medicine

gut microbiota-based biomarkers and fecal microbiota transplantation

as well as advancements in chimeri

c antigen receptor-T (CAR-T) cell therapy. By summarizing the current status and progress of third-line treatment for mCRC

this review aims to inform clinical decision-making and guide future research directions.

关键词

Keywords

references

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