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中华妇幼临床医学杂志(电子版) ›› 2025, Vol. 21 ›› Issue (04) : 386 -394. doi: 10.3877/cma.j.issn.1673-5250.2025.04.003

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晚期/复发性子宫内膜癌的分子靶向治疗联合免疫治疗的研究现状
林小娟1,2, 李清丽1,()   
  1. 1四川大学华西第二医院妇产科、出生缺陷与相关妇儿疾病教育部重点实验室,成都 610041
    2发育与妇儿疾病四川省重点实验室,成都 610041
  • 收稿日期:2025-02-27 修回日期:2025-06-29 出版日期:2025-08-01
  • 通信作者: 李清丽

Current landscape of targeted therapy combined with immunotherapy for advanced/recurrent endometrial cancer

Xiaojuan Lin1,2, Qingli Li1,()   

  1. 1Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
    2Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Chengdu 610041, Sichuan Province, China
  • Received:2025-02-27 Revised:2025-06-29 Published:2025-08-01
  • Corresponding author: Qingli Li
  • Supported by:
    Natural Science Foundation of Sichuan Province(2025ZNSFSC0541)
引用本文:

林小娟, 李清丽. 晚期/复发性子宫内膜癌的分子靶向治疗联合免疫治疗的研究现状[J/OL]. 中华妇幼临床医学杂志(电子版), 2025, 21(04): 386-394.

Xiaojuan Lin, Qingli Li. Current landscape of targeted therapy combined with immunotherapy for advanced/recurrent endometrial cancer[J/OL]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2025, 21(04): 386-394.

晚期/复发性子宫内膜癌(AEC/REC)患者的传统治疗方案疗效有限,是妇科肿瘤领域的重要挑战。以铂类药物为基础的联合化疗作为AEC/REC的传统一、二线方案,存在患者的客观缓解率(ORR)不高、缓解持续时间(DOR)短等局限,亟需探索新的治疗策略。免疫检查点抑制剂(ICI)已成为临床针对AEC/REC微卫星高度不稳定(MSI-H)/错配修复缺陷(dMMR)亚型患者精准免疫治疗的突破性疗法;针对微卫星稳定(MSS)/错配修复功能正常(pMMR)亚型AEC/REC患者,ICI单药疗效欠佳,亟需探索更有效的联合增效治疗策略。笔者拟聚焦国内外关于AEC/REC患者分子靶向治疗联合免疫治疗的最新研究现状,通过协同作用机制探索、关键临床数据剖析、现有证据评估及趋势展望,深入探讨该领域当前研究焦点与难点问题,为AEC/REC患者临床治疗决策提供循证医学依据。

Advanced endometrial cancer/recurrent endometrial cancer (AEC/REC) has limited efficacy with conventional treatments and is a major challenge in gynecologic oncology. Platinum-based combination chemotherapy, as the traditional first- and second-line regimen, has limitations including suboptimal objective response rate (ORR) and short duration of response (DOR), highlighting the urgent to explore new strategies. Immune checkpoint inhibitors (ICI) show breakthrough efficacy in microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) subtypes, representing a key advance in precision immunotherapy. However, ICI monotherapy has poor efficacy in microsatellite stable (MSS)/mismatch repair-proficient (pMMR) subtypes, necessitating exploration of more effective combination strategies. This article systematically reviews the latest research status of targeted therapy combined with immunotherapy for AEC/REC domestically and internationally. Through exploring synergistic mechanisms, analyzing key clinical data, evaluating existing evidence, and forecasting trends, it deeply discusses current focal and challenging issues in this field, aiming to provide evidence-based support for clinical decision-making.

表1 AEC/REC患者分子靶向联合免疫治疗关键研究的治疗方案和生存结局
第1作者,发表年,研究代号 研究名称 患者纳入标准/组别 治疗方案 生存结局
Makker[3], 2023,309/ KEYNOTE-775 ①+②治疗经治AEC患者:Ⅲ期临床随机对照试验309/KEYNOTE-775的最新疗效与安全性数据更新 AEC/REC患者既往至少接受过一线铂类化疗/试验组(n=411) vs对照组(n=416) 试验组:口服①(20 mg,1次/d)+静脉输注②(200 mg,1次/3周)
对照组:化疗
总人群[mPFS:7.3个月vs 3.8个月(HR=0.56, 95%CI:0.48~0.66); mOS:18.7个月vs 11.9个月(HR=0.65, 95%CI:0.55~0.77)]
dMMR亚型[mPFS:10.7个月vs 3.7个月(HR=0.39, 95%CI:0.25~0.60); mOS:30.9个月vs 8.6个月(HR=0.43, 95%CI:0.28~0.68)]
pMMR亚型[mPFS:6.7个月vs 3.8个月(HR=0.60, 95%CI:0.50~0.72); mOS:18个月vs 12.2个月(HR=0.70, 95%CI:0.58~0.83)]
Marth[4], 2025,ENGOT-en9/LEAP-001 ①+②对比化疗用于AEC患者一线治疗:1项随机、开放标签、Ⅲ期临床试验 Ⅲ~Ⅳ期EC或REC患者/试验组(n=420) vs对照组(n=422) 试验组:口服①(20 mg,1次/d+静脉输注②(200 mg,1次/3周)
对照组:卡铂+紫杉醇(1次/3周)
总人群[mPFS:12.5个月vs 10.2个月(HR=0.91, 95%CI:0.76~1.09); mOS:37.7个月vs 32.1个月(HR=0.93, 95%CI:0.77~1.12)]
dMMR亚型[mPFS:31.8个月vs 9.0个月(HR=0.61, 95%CI:0.40~0.92); mOS:NR vs NR(HR=0.57,95%CI:0.36~0.91)]
pMMR亚型[mPFS:9.6个月vs 10.2个月(HR=0.99, 95%CI:0.82~1.21); mOS:30.9个月vs 29.4个月(HR=1.02,95%CI:0.83~1.26)]
Wei[7], 2022,NCT04157491 ③+④治疗AEC/REC患者的有效性、安全性及生物标志物分析:Ⅱ期临床试验 接受至少一线(无上限)标准铂类化疗期间或之后出现疾病进展的AEC/REC患者/试验组(n=23) 试验组:口服④(12 mg,1次/d,d1~14,21 d为1个治疗周期)+静脉滴注③(200 mg,1次/3周) 总人群(ORR=73.9%,95%CI:51.6%~89.8%; DCR=91.3%, 95%CI:72.0%~98.9%; mPFS:NR; 12个月PFS率=57.1%, 95%CI:33.6%~75.0%)
MSI-H/dMMR亚型(ORR=100%)
MSS/pMMR亚型(ORR=57.1%)
Tian[8],2024,CAP 04 ⑤+⑥治疗至少1种系统治疗失败后的AEC/REC患者:单臂Ⅱ期临床试验 ≥1种既往系统治疗失败的AEC/REC患者/试验组(n=36) 试验组:口服⑥(250 mg,1次/d)+静脉滴注⑤(200 mg,1次/2周) 总人群(ORR=44.4%, 95%CI:27.9%~61.9%; DCR=91.7%, 95%CI:77.5%~98.2%;mPFS:6.2个月,95%CI:5.3~11.1个月;mOS:21.0个月,95%CI:13.4个月至NR)
Westin[9],2024,DUO-E ⑦+卡铂/紫杉醇,序贯⑦维持治疗联合或不联合⑧用于AEC患者的一线治疗:Ⅲ期临床试验 Ⅲ~Ⅳ期EC或REC患者/试验组(n=239) vs度伐利尤单抗组(n=238) vs对照组(n=241) 试验组:静脉滴注度⑦(1 120 mg)+卡铂与紫杉醇(1次/3周,共6次);维持治疗-静脉滴注⑦(1 500 mg,1次/4周)+口服⑧(300 mg,2次/d)
度伐利尤单抗组:静脉滴注⑦(1 120 mg)+卡铂与紫杉醇(1次/3周);维持治疗-静脉滴注⑦(1 500 mg,1次/4周)
对照组:卡铂+紫杉醇(1次/3周)
总人群(mPFS:15.1个月vs 10.2个月vs 9.6个月;mOS:NR vs NR vs 25.9个月)
dMMR亚型(mPFS:31.8个月vs NR vs 7.0个月)
pMMR亚型(mPFS:15个月vs 9.9个月vs 9.7个月)
Lheureux[10], 2022,NCT03367741 ⑨+⑩治疗AEC/REC患者的转化性随机Ⅱ期临床试验 AEC/REC患者既往至少接受过一线铂类化疗/试验组(n=36) vs对照组(n=18) 试验组:28 d为1个治疗周期,口服⑨(40 mg,1次/d)+静脉滴注纳⑩(240 mg,1次/2周,连续4次,然后剂量调整为480 mg,1次/4周)
对照组:静脉滴注⑩(240 mg,1次/2周,连续4次,然后剂量调整为480 mg,1次/4周)
总人群[mPFS:5.3个月vs 1.9个月(HR=0.59, 95%CI:0.36~0.98)]
Wu,2024/ASCO年会摘要5619,NCT03903705 ⑪+③单抗治疗pMMR型AEC患者的疗效:1项多中心、单臂Ⅱ期临床试验结果 AEC/REC患者既往至少接受过一线铂类化疗/试验组(n=98) 试验组:口服⑪(5 mg,1次/d,d1~14,21 d为1个治疗周期)+静脉滴注③(200 mg,1次/3周) 总人群(ORR=35.6%, 95%CI:25.6%~46.6%; DCR=88.5%, 95%CI:79.9%~94.3%;mPFS:9.5个月,95%CI:5.6个月至NR; mOS:21.3个月(95%CI:17.3个月至NR)
Wu,2024/IGCS年会摘要1577,NCT04574284 ⑫+④治疗AEC/REC患者:1项多队列、开放标签、多中心Ⅱ期临床试验 AEC/REC患者既往至少接受过一线铂类化疗/试验组(n=85) 试验组:脉滴注⑫(1 200 mg,1次/3周)+口服④(12 mg,1次/d,d1~14,21 d为1个治疗周期) 非MSI-H/dMMR型(ORR=31.76%; mPFS:8.38个月;mOS:21.72个月)
Wen,2024/ASCO年会摘要5597),NCT05112991 ⑬+①治疗一线含铂化疗失败的EC患者的疗效与安全性 AEC/REC患者既往至少接受过一线铂类化疗/试验组(n=32) 试验组:口服①(20 mg,1次/d)+皮下注射⑬(400 mg,1次/4周) 非MSI-H/dMMR型(ORR=40.0%, 95%CI:21.1%~61.3%; DCR=84.0%, 95%CI:63.9%~95.5%; mPFS:9.2个月,95%CI:4.0~11.0个月)
Lan等,2025/SGO年会摘要864114,NCT05824481 ⑭+①治疗AEC:1项多中心、单臂Ⅱ期临床试验 AEC/REC患者既往至少接受过一线铂类化疗/试验组(n=28) 试验组:口服①(16 mg或12 mg, 1次/d)+静脉滴注⑭(10 mg/kg,1次/3周) 总人群(ORR=42.9%, 95%CI:24.5%~62.8%; DCR=92.9%, 95%CI:76.5%~99.1%; mPFS:NR; mOS:NR)
[1]
Cathalijne CPA, Tjalling B, Carien LC, et al. PARP and PD-1/PD-L1 checkpoint inhibition in recurrent or metastatic endometrial cancer[J]. Crit Rev Oncol Hematol, 2020, 152: 102973. DOI: 10.1016/j.critrevonc.2020.102973.
[2]
Makker V, Colombo N, Casado HA, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer[J]. N Engl J Med, 2022, 386(5): 437-448. DOI: 10.1056/NEJMoa2108330.
[3]
Makker V, Colombo N, Casado HA, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase Ⅲ study 309/KEYNOTE-775[J]. J Clin Oncol, 2023, 41(16): 2904-2910. DOI: 10.1200/JCO.22.02152.
[4]
Marth C, Moore RG, Bidzinski M, et al. First-line lenvatinib plus pembrolizumab versus chemotherapy for advanced endometrial cancer: a randomized, open-label, phase Ⅲ trial [J]. J Clin Oncol, 2025, 43(9): 1083-1100. DOI: 10.1200/JCO-24-01326.
[5]
Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer[J]. N Engl J Med, 2023, 388(23): 2159-2170. DOI: 10.1056/NEJMoa2302312.
[6]
Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer[J]. N Engl J Med, 2023, 388(23): 2145-2158. DOI: 10.1056/NEJMoa2216334.
[7]
Wei W, Ban X, Yang F, et al. Phase Ⅱ trial of efficacy, safety and biomarker analysis of sintilimab plus anlotinib for patients with recurrent or advanced endometrial cancer[J]. J Immunother Cancer, 2022, 10(5): e004338. DOI: 10.1136/jitc-2021-004338.
[8]
Tian W, Ren Y, Lu J, et al. Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy (CAP 04): a single-arm phase Ⅱ trial[J]. BMC Med, 2024, 22(1): 344. DOI: 10.1186/s12916-024-03564-z.
[9]
Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase Ⅲ DUO-E trial[J]. J Clin Oncol, 2024, 42(3): 283-299. DOI: 10.1200/JCO.23.02132.
[10]
Lheureux S, Matei DE, Konstantinopoulos PA, et al. Translational randomized phase Ⅱ trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer[J]. J Immunother Cancer, 2022, 10(3): e004233. DOI: 10.1136/jitc-2021-004233.
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