2023年度妇科恶性肿瘤治疗进展及展望

doi:10.19401/j.cnki.1007-3639.2024.04.002

中国癌症杂志 ›› 2024, Vol. 34 ›› Issue (4): 340-360.doi: 10.19401/j.cnki.1007-3639.2024.04.002

2023年度妇科恶性肿瘤治疗进展及展望

冯征(), 郭勤浩, 朱俊, 吴小华, 温灏()

复旦大学附属肿瘤医院妇瘤科，复旦大学上海医学院肿瘤学系，上海 200032

收稿日期:2024-03-12 修回日期:2024-04-06 出版日期:2024-04-30 发布日期:2024-05-17
通信作者: 温灏（ORCID: 0000-0002-9587-8742），副主任医师，复旦大学附属肿瘤医院妇瘤科副主任。
作者简介:冯征（ORCID: 0000-0003-2561-3869），主治医师。
吴小华，医学博士，主任医师，教授，博士研究生导师。现任复旦大学附属肿瘤医院妇瘤科主任、妇科肿瘤多学科综合治疗组首席专家，上海市优秀学科带头人，上海市医学领军人才。现任中国抗癌协会卵巢癌专业委员会主任委员、中国初级卫生保健基金会妇科专业委员会主任委员、中国临床肿瘤学会理事、上海市抗癌协会常务理事、中国抗癌协会妇科肿瘤专业委员会前任主任委员及上海市抗癌协会妇科肿瘤专业委员会前任主任委员。曾任国际妇科癌症学会教育委员会委员、亚太地区理事候选人、美国妇科肿瘤学会国际委员会委员、美国西北大学Feinberg医学院妇产科学系兼职教授等。目前还担任International Journal of Gynecological Cancer、Cancer Medicine、Journal of Gynecological Oncology等英文杂志和《中华妇产科杂志》《中华解剖与临床杂志》《中国癌症杂志》等中文杂志编委，美国国家综合癌症网络（National Comprehensive Cancer Network，NCCN）妇科肿瘤临床指南国际审阅专家。
温灏，医学博士、副主任医师、硕士研究生导师。现任复旦大学附属肿瘤医院肿瘤妇科行政副主任，复旦大学附属肿瘤医院福建医院妇科肿瘤诊治中心常务副主任。兼任中国抗癌协会子宫体肿瘤专业委员会常务委员、中国抗癌协会肿瘤标志专业委员会妇科肿瘤标志物专家学组副组长、中国抗癌协会青年理事会理事、中国初级卫生保健基金会妇科专委会常务委员及秘书长、中国妇幼健康研究会妇产科精准医疗专业委员会委员、中国优生优育协会妇产专业委员会委员、中国医药教育协会肿瘤药物临床研究评价专委会委员、中国老年保健协会肿瘤防治和临床研究管理专业委员会委员、上海市抗癌协会妇科肿瘤专业委员会候任主任委员、上海市抗癌协会青年理事会理事、上海市抗癌协会肿瘤药物临床研究专委会委员、上海研究型医院学会妇产科转化医学研究与发展专委会副主任委员、上海市医学会妇科肿瘤分会卵巢癌学组副组长。担任Gynecology and Pelvic Medicine、《现代妇产科进展》《肿瘤药学》《肿瘤综合治疗电子杂志》等杂志编委，《中国癌症杂志》青年编委、《临床肿瘤学杂志（JCO）》中文版妇瘤专刊青年编委。
基金资助:
上海市自然科学基金(21ZR1415000)

Progress in treatment of gynecological cancer in 2023

FENG Zheng(), GUO Qinhao, ZHU Jun, WU Xiaohua, WEN Hao()

Department of Gynecological Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Received:2024-03-12 Revised:2024-04-06 Published:2024-04-30 Online:2024-05-17
Contact: WEN Hao

摘要/Abstract

摘要：

对比中国与全球情况可知，中国癌症发病率与世界平均水平接近，但死亡率与全球平均水平有差异。中国妇科恶性肿瘤负担日益加重，城乡差异较大，地区分布不均衡，癌症防控形势严峻。近年来，新技术、新药物[如免疫检查点抑制剂（immune checkpoint inhibitor，ICI）、抗体-药物偶联物（antibody-drug conjugate，ADC）等]陆续进入临床，为妇科恶性肿瘤的治疗带来新希望。本文对2023年度妇科恶性肿瘤的重大研究进展进行梳理，其中，在宫颈癌治疗方面，本文回顾了标准治疗模式革新、晚期复发转移性宫颈癌后线治疗的相关进展（ENGOT-cx11/GOG-3047/KEYNOTE-A18、KEYNOTE-826研究等）；在卵巢癌治疗方面，本文总结了PARP抑制剂及免疫治疗、新诊断卵巢癌一线治疗、复发性卵巢癌治疗的最新进展（FLAMES、ANITA/ENGOT-Ov41/GEICO 69-O、NRG-GY004研究等）；而在子宫内膜癌治疗方面，本文按照局部晚期子宫内膜癌治疗（GOG 258、Lunchbox研究等）、晚期/复发转移性子宫内膜癌治疗方面的进展（如ENGOT-EN6-NSGO/GOG-3031/RUBY研究等）进行综述，并对后线靶向治疗和免疫治疗探索进行总结（如KEYNOTE-775、ADAGIO等研究）。本文从上述方面对妇科肿瘤2023年度的进展进行述评，旨在为临床实践及临床研究的开展提供参考。

关键词: 宫颈癌, 卵巢癌, 子宫内膜癌, 治疗进展

Abstract:

Compared with the global situation, it can be found that the cancer incidence in China is close to the world average level, but the mortality rate has difference compared with the global average level. The burden of gynecological cancers in China is increasing, with large differences between urban and rural areas and uneven regional distribution. Therefore, the situation of cancer prevention and control is still challenging. In recent years, new technologies and drugs, such as immune checkpoint inhibitors (ICIs) and antibody-drug conjugate (ADC), have been introduced into clinical practice, bringing new hope for the treatment of gynecological cancers. This article reviewed the major research progress of gynecological cancers in 2023. Among them, in terms of the progress of treatment for cervical cancer, we reviewed the innovation of standard treatment mode and the related progress of post-line treatment for advanced recurrent and metastatic cervical cancer (clinical research such as ENGOT-cx11/GOG-3047/KEYNOTE-A18, KEYNOTE-826). In terms of treatment for ovarian cancer, this review summarized the latest progress of PARP inhibitors, immunotherapy, first-line treatment of newly diagnosed ovarian cancer and treatment of recurrent ovarian cancer (FLAMES, ANITA/ENGOT-Ov41/GEICO 69-O, NRG-GY004, etc.). In terms of treatment for endometrial cancer, this study reviewed the progress in the treatment of locally advanced endometrial cancer (GOG 258, Lunchbox clinical research, etc.) and advanced/recurrent metastatic endometrial cancer (ENGOT-EN6-NSGO/GOG-3031/RUBY research, etc.), and summarized the exploration of back-line targeted immunotherapy (such as KEYNOTE-775, ADAGIO and other clinical studies). This study combed the progress of gynecological tumors in 2023 from the above aspects, aiming at providing reference for clinical practice and clinical research.

Key words: Cervical cancer, Ovarian cancer, Endometrial cancer, Progress in treatment

中图分类号:

R737.3

冯征, 郭勤浩, 朱俊, 吴小华, 温灏. 2023年度妇科恶性肿瘤治疗进展及展望[J]. 中国癌症杂志, 2024, 34(4): 340-360.

FENG Zheng, GUO Qinhao, ZHU Jun, WU Xiaohua, WEN Hao. Progress in treatment of gynecological cancer in 2023[J]. China Oncology, 2024, 34(4): 340-360.

图/表 7

表1

表2

2023年晚期复发转移性宫颈癌一线及后线治疗进展"

Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
KEYNOTE-826 (NCT03635567)	Persistent, recurrent, or metastatic cervical cancer	Phase Ⅲ randomized, double-blind, placebo-controlled trial	Pembrolizumab (MK-3475) plus chemotherapy versus chemotherapy plus placebo	mPFS with pembrolizumab-chemotherapy vs placebo-chemotherapy was 10.4 months vs 8.2 months (HR = 0.61, 95% CI: 0.50-0.74); mOS with pembrolizumab-chemotherapy vs placebo-chemotherapy was 26.4 months vs 16.8 months (HR = 0.63, 95% CI: 0.52-0.77)
SHR210-217 (NCT04680988)	Recurrent or metastatic cervical cancer	Randomized, open-label, 3-arm phase Ⅱ study	Camrelizumab ± famitinib vs physician's choice chemotherapy	ORR (BICR): 41.0% vs 24.1%; camrelizumab+famitinib vs camrelizumab, difference = 16.9%, P = 0.018 1 mPFS (BICR): 7.2 months vs 4.0 months; camrelizumab+famitinib vs camrelizumab, HR = 0.5 (0.4-0.8), P = 0.002 1 ORR (INV): 42.9%, 22.2%, and 14.3%, respectively; camrelizumab + famitinib vs camrelizumab, difference = 20.6%, P = 0.005 3 mPFS (INV): 8.1, 4.1 and 2.9 months, respectively, camrelizumab + famitinib vs camrelizumab, HR = 0.5 (0.3-0.7), P = 0.000 3 6-month OS rate: 90.5%, 86.5%, and 75.4%
AdvanTIG-202 (NCT04693234)	Previously treated recurrent or metastatic cervical cancer	Open-label, 2-cohort, multicenter, phase Ⅱ study	Tislelizumab and ociperlimab combination vs tislelizumab monotherapy	Tislelizumab±ociperlimab ORR was 22.5%, PD-L1⁺ subgroup ORR was 26.2%
InnovaTV 301/ENGOT-cx12/GOG-3057 (NCT04697628)	2L or 3L recurrent or metastatic cervical cancer	Global, randomized, open-label, phaseⅢ study	Tisotumab vedotin vs investigator’ s choice of chemotherapy	ORR: 17.8% vs 5.2% mOS: 11.5 months vs 9.5 months, HR = 0.70, 95% CI: 0.54-0.89, P = 0.003 8 mPFS: 4.2 months vs 2.9 months, HR = 0.67, 95% CI: 0.54-0.82, P<0.000 1

表2

表3

表4

2023年复发性卵巢癌治疗进展"

Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
ANITA/ENGOT-Ov41/GEICO 69-O (NCT03598270)	Recurrent ovarian, tubal, or peritoneal cancer and platinum treatment free interval of more than 6 months	Phase Ⅲ, randomized, double blinded trial	Platinum based chemotherapy with or without atezolizumab followed by niraparib maintenance with or without atezolizumab	PFS placebo+CT→placebo+ niraparib vs atezolizumab +CT→atezolizumab + niraparib: 10.1 months vs 11.2 months, HR = 0.89, P = 0.280 ORR placebo+CT→placebo+ niraparib vs atezolizumab+CT→atezolizumab + niraparib: 43% (95% CI: 36%-49%) vs 45% (95% CI: 39%-52%)
NRG-GY004 (NCT02446600)	Recurrent platinum-sensitive ovarian cancer	Randomized, open-label, phase Ⅲ trial	Olaparib with or without cediranib versus platinum-based chemotherapy	mPFS: 10.3 (95% CI: 8.7-11.2), 8.2 (95% CI: 6.6-8.7), and 10.4 (95% CI: 8.5-12.5) months with chemotherapy, olaparib, and olaparib+cediranib mOS: 32.7, 31.0 (HR = 1.27, P = 0.060), and 33.5 (HR = 1.12, P = 0.378) months with chemotherapy, olaparib, and olaparib+cediranib
NRG-GY023 (NCT04739800)	Platinum-resistant recurrent epithelial ovarian cancer, primary peritoneal or fallopian cancer who have received prior bevacizumab	Randomized phase Ⅱ trial	Triplet therapy (durvalumab in combination with olaparib and cediranib) compared to olaparib and cediranib or durvalumab and cediranib or standard of care chemotherapy	None of the experimental arms improved PFS in bevacizumab pre-exposed platinum resistant ovarian cancer patients
SORAYA (NCT04296890)	Platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression	Phase 3, single arm study	Mirvetuximab soravtansine (MIRV)	ORR: 32.4% (95% CI: 23.6-42.2) mDoR: 6.9 months (95% CI: 5.6-9.7)
MIRASOL (NCT04209855)	Platinum-resistant, high-grade serous ovarian cancer	Phase 3, global, confirmatory, open-label, randomized, controlled trial	Mirvetuximab soravtansine (MIRV) vs the investigator’s choice of chemotherapy	mPFS: 5.62 months (95% CI: 4.34-5.95) with MIRV and 3.98 months (95% CI: 2.86-4.47) with chemotherapy (P<0.001) ORR: 42.3% in the MIRV group and in 15.9% in the chemotherapy group (odds ratio, 3.81; 95% CI: 2.44-5.94; P<0.001) mOS: 16.46m with MIRV and 12.75m with chemotherapy; HR = 0.67; 95% CI: 0.50-0.89; P = 0.005
DESTINEY-PanTumor02 (NCT04482309)	HER2-expressing solid tumors (including cervical, endometrial, ovarian)	Phase Ⅱ, multicenter, open-label study	Trastuzumab deruxtecan (T-DXd)	In all patients, ORR: 37.1% (95% CI: 31.3-43.2), with responses in all cohorts mDOR: 11.3 months (95% CI: 9.6-17.8); mPFS: 6.9 months (95% CI: 5.6-8.0); mOS: 13.4 months (95% CI: 11.9-15.5)
OVAL study/GOG 3018 (NCT03398655)	Recurrent platinum-resistant ovarian cancer	Phase Ⅲ, randomized, controlled, double-arm, double-blind, multi-center study	Ofranergene obadenovec (VB-111) combined with paclitaxel vs paclitaxel combined with placebo	mPFS: 5.29 months in the ofranergene obadenovec arm and 5.36 months in the control arm, HR = 1.03 (CI: 0.83-1.29; P = 0.782 3) mOS: ofranergene obadenovec was 13.37 months vs 13.14 months, HR = 0.97 (CI: 0.75-1.27; P = 0.844 0) ORR (RECIST 1.1): 28.9% with ofranergene obadenovec vs 29.6% with control

表4

表5

表6

2023年晚期/复发转移性子宫内膜癌治疗进展"

Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
ENGOT-EN6-NSGO/GOG-3031/RUBY (NCT03981796)	Recurrent or primary advanced endometrial cancer	Phase Ⅲ, randomized, double-blind, multicenter study	Dostarlimab plus carboplatin-paclitaxel vs placebo plus carboplatin-paclitaxel	dMMR-MSI-H PFS rate at 24 months: 61.4% (95% CI: 46.3-73.4) in the dostarlimab group and 15.7% (95% CI: 7.2-27.0) in the placebo group (HR = 0.28; 95% CI: 0.16-0.50, P<0.001) In the overall population, PFS rate at 24 months was 36.1% (95% CI: 29.3-42.9) in the dostarlimab group and 18.1% (95% CI: 13.0-23.9) in the placebo group (HR = 0.64, 95% CI: 0.51-0.80, P<0.001)
NRG-GY018 (NCT03914612)	Measurable disease (stage Ⅲ or ⅣA) or stage ⅣB or recurrent endometrial cancer	Double-blind, placebo-controlled, randomized, phase 3 trial	Pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin	dMMR was 12 months PFS rate was 74% in the pembrolizumab group and 38% in the placebo group (HR = 0.30, 95% CI: 0.19-0.48, P<0.001) pMMR mPFS was 13.1 months with pembrolizumab and 8.7 months with placebo (HR = 0.54, 95% CI: 0.41-0.71, P<0.001)
ENGOT-en7/MaNGO/AtTEnd (NCT03603184)	Advanced/recurrent endometrial cancer conditions	Phase Ⅲ double-blind randomized placebo controlled Trial	Atezolizumab in combination with paclitaxel and carboplatin	dMMR PFS，NE vs 6.9 months (atezolizumab vs placebo, HR = 0.36, 95% CI: 0.23-0.57, P = 0.000 5) ITT PFS, 10.1 months vs 8.9 months (atezolizumab vs placebo, HR = 0.74, 95% CI: 0.61-0.91, P = 0.021 9) ITT interim OS: 38.7 months vs 30.2 months (maturity 43%, HR = 0.82, 95% CI: 0.63-1.07, P = 0.048 3)
DUO-E/GOG-3041/ENGOT-EN10 (NCT04269200)	Newly diagnosed advanced or recurrent endometrial cancer	Phase Ⅲ, global, double-blind, placebo-controlled trial	Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib	ITT PFS benefit was observed in the durvalumab (HR = 0.71, P = 0.003) and durvalumab + olaparib arms (HR = 0.55, P<0.001) vs control dMMR PFS: durvalumab vs control, HR = 0.42; durvalumab + olaparib vs control, HR = 0.41 pMMR PFS: durvalumab vs control, HR = 0.77; durvalumab + olaparib vs control, HR = 0.57 Interim overall survival results (maturity approximately 28%): durvalumab vs control, HR = 0.77, P = 0.120; durvalumab + olaparib vs control, HR = 0.59, P = 0.003 ITT mPFS 10.2 months vs 9.6 months (durvalumab arm vs control, HR = 0.71, P = 0.003); 15.1 months vs 9.6 months (durvalumab + olaparib arm vs control, HR = 0.55, P<0.001)

表6

表7

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Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
SHAPE (NCT01658930）	Low-risk early-stage cervical cancer (LRESCC)	International randomized phase Ⅲ trial	Radical hysterectomy and pelvic node dissection (RH) vs simple hysterectomy and pelvic node dissection (SH)	ITT PRR3 analysis: 2.52% with SH vs 2.17% with RH (DPRR3 0.35% with 95% UCL 2.32%) 3-year ERFS and OS were respectively 98.1% and 99.1% with SH; 99.7% and 99.4% with RH
ENGOT-cx11/GOG-3047/ KEYNOTE-A18 (NCT04221945)	Newly diagnosed, previously untreated, high-risk locally advanced cervical cancer	Randomized, phase 3, double-blind study	Pembrolizumab or placebo + CCRT, then pembrolizumab or placebo	24-month PFS was 67.8% with pembrolizumab + CCRT vs 57.3% with placebo + CCRT; median PFS was not reached in either group (HR = 0.70, 95% CI: 0.55-0.89, P = 0.002 0) Pembrolizumab to CCRT showed a favorable trend in OS (HR = 0.73, 95% CI: 0.49-1.07, 42.9% maturity)
CALLA (NCT03830866)	Locally advanced cervical cancer	Randomized, multi-center, double-blind, placebo-controlled, global, phase Ⅲ study	Durvalumab + standard of care (SoC) or placebo + Soc, followed by durvalumab/placebo maintenance for 24 months	Durvalumab+CRT did not show a statistically significant improvement in PFS vs placebo+CRT (HR = 0.84, 95% CI: 0.65-1.08, P = 0.174)
GCIG INTERLACE (CRUK grant number: C37815/A12832)	Locally advanced cervical cancer	Randomized, phase Ⅲ study	CRT alone vs induction chemotherapy + CRT	PFS at 5 years: 73% vs 64%, HR = 0.65, 95% CI: 0.46-0.91, P = 0.013 OS at 5 years: 80% vs 72%, HR = 0.61, 95% CI: 0.40-0.91, P = 0.040

Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
FLAMES (NCT04169997)	Newly diagnosed Ⅲ/Ⅳ high-grade serous ovarian carcinoma (HGSOC)	Phase Ⅲ randomized, double-blind, placebo-controlled, multicenter study	Senaparib vs placebo	PFS (BICR): NR vs 13.6 months, HR = 0.43, 95% CI: 0.32-0.58; P<0.000 1
DUO-O/ENGOT-Ov46 (NCT03737643)	Newly diagnosed advanced ovarian cancer patients	Phase Ⅲ randomised, double-blind, multi-center study	Durvalumab in combination with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib	PC + bevacizumab + durvalumab+olaparib vs PC + bevacizumab, mPFS: 24.2 months vs 19.3 months, HR = 0.63，95% CI: 0.52-0.76; P<0.000 1

Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
GOG 258 (NCT00942357)	Stage Ⅲ or ⅣA endometrial carcinoma	Randomized, multicenter, phase 3 trial	6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) vs 6 cycles of combination chemotherapy alone	Chemoradiotherapy did not improve OS compared to chemotherapy (HR = 1.05; 95% CI: 0.82-1.34) Chemoradiotherapy did not improve PFS compared to chemotherapy (HR = 0.9, 95% CI: 0.74-1.1)
Lunchbox (NCT02501954)	Optimally debulked advanced endometrial carcinoma	Randomized phase Ⅲ trial	Cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs sandwich therapy of carboplatin and paclitaxel followed by tumor volume directed irradiation then further carboplatin and paclitaxel	PFS (P = 0.576 5), OS (P = 0.550)

Official title	Inclusion criteria	Study design	Intervention/treatment	Primary endpoint
KEYNOTE-775 (NCT03517449)	Advanced endometrial cancer who had previously received at least one platinum-based chemotherapy	Multicenter, open-label, phase 3	Lenvatinib plus pembrolizumab or chemotherapy of the treating physician’s choice	pMMR population mPFS: 6.6 months vs 3.8 months (lenvatinib plus pembrolizumab vs chemotherapy, HR = 0.60, 95% CI: 0.50-0.72, P<0.001); overall: 7.2 months vs 3.8 months (HR = 0.56; 95% CI: 0.47-0.66, P<0.001) pMMR population mOS: 17.4 months vs 12.0 months (lenvatinib plus pembrolizumab vs chemotherapy, HR = 0.68, 95% CI: 0.56-0.84, P <0.001); overall: 18.3 months vs 11.4 months (HR = 0.62, 95% CI: 0.51-0.75, P<0.001) pMMR ORR: lenvatinib plus pembrolizumab (32.4%) than with chemotherapy (15.1%), all-comer population (33.8% vs 14.7%)
ADAGIO (NCT04590248)	Recurrent or persistent uterine serous carcinoma	Phase 2b, open-label, single-arm, multi-center study	Adavosertib	ORR (by BICR) was 26%, DcR (by BICR) was 51.4%, mPFS was 2.8 months, mOS was 9.6 months
DESTINY-PanTumor02 (NCT04482309)	HER2-expressing solid tumors (including cervical, endometrial, ovarian)	Phase Ⅱ, multicenter, open-label study	Trastuzumab deruxtecan (T-DXd)	ORR 57.5%, 12 weeks DCR rate 80% HER2 IHC 3+ ORR 84.6%

2023年度妇科恶性肿瘤治疗进展及展望

Progress in treatment of gynecological cancer in 2023

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