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

doi:10.3877/cma.j.issn.1673-5250.2025.04.003

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.

Key words: Endometrial neoplasms, Advanced/recurrent endometrial cancer, Molecular targeted therapy, Immunotherapy, Immune checkpoint inhibitors, Molecular classification of endometrial cancer, Microsatellite instability-high, Deficient mismatch repair, Multi-target tyrosine kinase inhibitors, Poly (ADP-ribose) polymerase inhibitor

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)

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)

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