放疗暴露对呋喹替尼联合信迪利单抗治疗难治性微卫星稳定转移性结直肠癌的影响：一项前瞻性观察研究。
Effect of radiotherapy exposure on fruquintinib plus sintilimab treatment in refractory microsatellite stable metastatic colorectal cancer: a prospective observation study.
作者信息
Cheng Mingxia, Jin Min, Yang Shengli, Zhao Lei, Yu Dandan, Lin Zhenyu, Li Pindong, Huang Chuying, Liu Junli, Wang Jing, Xue Jun, Ma Hong, Hu Jianli, Yang Kunyu, Zhang Tao, Liu Hongli
机构信息
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
出版信息
J Immunother Cancer. 2025 Jan 4;13(1):e009415. doi: 10.1136/jitc-2024-009415.
BACKGROUND
Immune checkpoint inhibitors (ICIs) in combination with antiangiogenic drugs have shown promising outcomes in the third-line and subsequent treatments of patients with microsatellite stable metastatic colorectal cancer (MSS-mCRC). Radiotherapy (RT) may enhance the antitumor effect of immunotherapy. However, the effect of RT exposure on patients receiving ICIs and targeted therapy remains unclear. This study aimed to investigate the association between RT exposure and clinical responses to fruquintinib (a highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor) plus sintilimab (an anti-programmed death 1 antibody; F&S) in previously treated patients with MSS-mCRC and to explore predictive biomarkers.
METHODS
In this prospective observational study, patients with mCRC receiving F&S as third-line or subsequent treatment were enrolled. Eligible patients were divided into the RT cohort (RTC) and the non-RT cohort (NRTC) according to their RT history. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Pretreatment fecal and serum samples were collected for microbiome analysis, metabolome analysis, and immune signatures to identify biomarkers for treatment.
RESULTS
A total of 55 patients were included, of which 25 were in the RTC and 30 in the NRTC. Better ORR (28.0% vs 6.7%, p=0.048), DCR (80.0% vs 36.7%, p=0.002), median PFS (6.2 vs 2.7 months, p<0.001), and median OS (14.8 vs 5.9 months, p=0.019) were noted in patients with RTC than those with NRTC. The enrichment of , , and PC(20:5(5Z,8Z,11Z,14Z,17Z)/20:3(8Z,11Z,14Z)) in RTC significantly predicted better DCR and PFS, whereas guanosine and interleukin-10 predominated in patients with NRTC were negatively correlated with PFS and OS.
CONCLUSIONS
Patients with RT exposure benefited significantly from F&S in the third-line or subsequent treatment for MSS-mCRC. Gut microbiota, metabolites, and cytokines may help predict F&S outcomes for mCRC, which may be helpful in treatment decision-making.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov identifier: NCT05635149.
背景
免疫检查点抑制剂（ICIs）联合抗血管生成药物在微卫星稳定转移性结直肠癌（MSS - mCRC）患者的三线及后续治疗中显示出了有前景的疗效。放射治疗（RT）可能会增强免疫治疗的抗肿瘤效果。然而，RT暴露对接受ICIs和靶向治疗的患者的影响仍不清楚。本研究旨在调查RT暴露与既往接受过治疗的MSS - mCRC患者接受呋喹替尼（一种高度选择性的血管内皮生长因子受体酪氨酸激酶抑制剂）联合信迪利单抗（一种抗程序性死亡1抗体；F&S）治疗的临床反应之间的关联，并探索预测生物标志物。
方法
在这项前瞻性观察性研究中，纳入了接受F&S作为三线或后续治疗的mCRC患者。符合条件的患者根据其放疗史分为放疗队列（RTC）和非放疗队列（NRTC）。主要终点是客观缓解率（ORR）。次要终点包括疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）和安全性。收集治疗前的粪便和血清样本进行微生物组分析、代谢组分析和免疫特征分析，以识别治疗的生物标志物。
结果
共纳入了55例患者，其中25例在RTC，30例在NRTC。RTC患者的ORR（28.0%对6.7%，p = 0.048）、DCR（80.0%对36.7%，p = 0.002）、中位PFS（6.2对2.7个月，p < 0.001）和中位OS（14.8对5.9个月，p = 0.019）均优于NRTC患者中的相应指标。RTC中 、 和PC(20:5(5Z,8Z,11Z,14Z,17Z)/20:3(8Z,11Z,14Z))的富集显著预测了更好的DCR和PFS，而NRTC患者中占主导的鸟苷和白细胞介素 - 10与PFS和OS呈负相关。
结论
在MSS - mCRC的三线或后续治疗中，接受过RT暴露的患者从F&S治疗中显著获益。肠道微生物群、代谢物和细胞因子可能有助于预测mCRC患者接受F&S治疗的结果，这可能有助于治疗决策。
试验注册号
ClinicalTrials.gov标识符：NCT05635149。
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