对于HR阳性HER2阴性晚期乳腺癌患者，指南推荐首选CDK4/6抑制剂联合内分泌治疗，对于内分泌耐药或不适合内分泌治疗患者，首选治疗方案仍然是单药化疗，但是该方法并非都能带来总生存获益，且伴有严重毒性反应。
近年来，抗体缀合药物问世，将若干小分子强毒性化疗药物缀合于大分子靶向单克隆抗体，既可提高对癌细胞的杀伤力，又可降低对正常细胞的毒性。
TROPiCS-02研究证实，对于HR阳性HER2阴性晚期乳腺癌化疗、内分泌治疗、CDK4/6抑制剂耐药患者，TROP2抗体缀合药物戈（维替康）沙妥珠单抗与单药化疗相比，中位无进展生存延长1.5个月、进展或死亡风险减少34%，中位总生存延长3.2个月、总死亡风险减少21%。
DESTINY-Breast04研究证实，对于HER2低表达晚期乳腺癌化疗失败患者，HER2抗体缀合药物德（鲁替康）曲妥珠单抗与单药化疗相比，中位无进展生存延长4.8个月、进展或死亡风险减少50%，中位总生存延长6.6个月、总死亡风险减少36%，HR阳性患者中位无进展生存4.7个月、进展或死亡风险减少49%，中位总生存延长6.4个月、总死亡风险减少36%。
DESTINY-Breast06研究证实，对于HR阳性HER2低或超低表达晚期乳腺癌内分泌治疗耐药尚未化疗患者，德曲妥珠单抗与单药化疗相比，中位无进展生存延长5.1个月、进展或死亡风险减少37%。
虽然这些药物扩大了内分泌治疗和（或）化疗后治疗选择，但是总生存延长仍然不多。那么，将德鲁替康缀合于TROP2抗体达博妥单抗能否带来惊喜？
2年前，TROPION-Breast01研究证实，对于HR阳性HER2阴性乳腺癌不可手术或远处转移经过一或二线化疗患者，德（鲁替康）达博妥单抗与单药化疗相比，截至2023年7月17日，中位无进展生存延长2个月，进展或死亡风险减少37%，总生存尚未达到中位。
TROPION-Breast01 (NCT05104866): A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator’s Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy
2025年12月23日，欧洲肿瘤内科学会官方期刊《肿瘤学年鉴》在线发表中国工程院院士中国医学科学院肿瘤医院徐兵河、中山大学肿瘤防治中心王树森、台湾大学医学院附属医院卢彦伸以及法国、美国、韩国、西班牙、意大利、巴西、加拿大、日本、英国学者的TROPION-Breast01研究最终总生存分析结果。
该国际多中心非盲随机对照三期临床研究于2021年10月18日至2022年12月26日从全球167家医院入组HR阳性HER2阴性乳腺癌不可手术或远处转移经过一或二线化疗患者732例，按1比1随机分为两组：德达博妥单抗组365例（每3周6mg/kg）、单药化疗组367例（艾立布林、卡培他滨、长春瑞滨、吉西他滨四选一），治疗直至进展或毒性无法耐受。两个主要终点为盲法独立集中审核无进展生存和总生存，次要终点包括研究者评定无进展生存、客观缓解率、缓解持续时间、12周疾病控制率、首次和再次后续治疗或死亡时间以及再次疾病进展或死亡时间、安全性。
结果，截至2024年7月24日，中位随访22.8个月，德达博妥单抗组与单药化疗组相比：
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中位总生存：18.6个月比18.3个月（95%置信区间：17.3～20.1、17.3～20.5）
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总死亡风险：增加1%（风险比：1.01，95%置信区间：0.83～1.22，P=0.9445）
根据事后分析发现，两组后续抗体缀合药物治疗（德曲妥珠单抗和戈沙妥珠单抗）比例不平衡：德达博妥单抗组仅12.3%，单药化疗组达24.0%。
再对后续抗体缀合药物治疗进行逆概率删失加权分析，德达博妥单抗组与单药化疗组相比：
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中位总生存：19.1个月比17.5个月
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总死亡风险：减少14%（校正后风险比：0.86，95%置信区间：0.70～1.06）
根据事先计划HER2零表达或低表达探索性分析，德达博妥单抗组与单药化疗组相比：
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HER2零表达
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中位总生存：17.8个月比14.3个月（95%置信区间：15.8～20.4、12.1～21.0）
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总死亡风险：减少11%（风险比：0.89，95%置信区间：0.64～1.24）
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HER2低表达
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中位总生存：19.0个月比18.7个月（95%置信区间：16.4～21.3、17.4～22.6）
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总死亡风险：增加6%（风险比：1.06，95%置信区间：0.79～1.43）
根据本次最终分析，次要疗效终点仍然有利于德达博妥单抗组。德达博妥单抗组与单药化疗组相比，总体安全性仍然良好，≥3级治疗相关不良事件发生率为20.8%比44.7%，治疗相关不良事件所致剂量减少和治疗中断较少，且更长随访期未见新的安全问题。
因此，该研究结果表明，HR阳性HER2阴性乳腺癌不可手术或远处转移经过一或二线化疗患者，德达博妥单抗与单药化疗相比，主要终点之一无进展生存获益，主要终点之二总生存未见显著获益，事后分析后续抗体缀合药物治疗可能影响总生存，结合安全数据，研究者支持德达博妥单抗作为此类患者新的治疗选择。用低情商的说法，该研究结果令人无语！用高情商的说法，该研究结果两组难治患者其实都得到了很好的治疗！
据悉，国家药品监督管理局已于2025年8月19日批准德达博妥单抗上市，适用于治疗既往接受过内分泌治疗且在晚期疾病阶段接受过至少一线化疗的不可切除或转移性的HR阳性HER2阴性乳腺癌成人患者，为相关患者提供了新的治疗选择。
相关链接
Ann Oncol. 2025 Dec 23. IF: 65.4
Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone-receptor-positive HER2-negative breast cancer: final overall survival analysis of the phase 3 TROPION-Breast01 study.
Pistilli B, Jhaveri K, Im SA, Pernas S, De Laurentiis M, Wang S, Martínez Janez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Tsurutani J, Kalinsky K, Rubini Liedke PE, Carroll D, Khan S, Rugo HS, Xu B, Bardia A; TROPION-Breast01 investigators.
Gustave Roussy Cancer Center, Villejuif, France; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Sarah Cannon Research Institute, Nashville, TN, USA; Winship Cancer Institute at Emory University, Atlanta, GA, USA; AstraZeneca, Gaithersburg, MD, USA; University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Previously Massachusetts General Hospital Cancer Center, Boston, MA, USA; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University, Seoul, Korea; Institut Català d’Oncologia, IDIBELL, L’Hospitalet, Barcelona, Spain; Ramón y Cajal University Hospital, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Istituto Nazionale Tumori IRCCS “Fondazione Pascale”, Naples, Italy; Cancer Center of Sun Yat-sen University, Guangzhou, China; National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, China; Catarina Pesquisa Clínica, Itajaí, SC, Brazil; Hospital das Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; UPCO – Pesquisa Clinica em Oncologia, Porto Alegre, RS, Brazil; Oncoclinicas Porto Alegre, Porte Alegre, RS, Brazil; Princess Margaret Cancer Centre/UHN, Toronto, ON, Canada; Aichi Cancer Center, Nagoya, Japan; Aichi Breast Clinic Hirabari, Nagoya, Japan; Advanced Cancer Translational Research Institute, Showa Medical University, Tokyo, Japan; AstraZeneca, Cambridge, United Kingdom.
HIGHLIGHTS
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In TROPION-Breast01, Dato-DXd demonstrated a statistically significant improvement in PFS by BICR compared with ICC
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The dual primary endpoint of OS was not statistically significant; subsequent ADC treatment may have affected OS results
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Secondary efficacy endpoints continued to favor Dato-DXd at this final analysis
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The Dato-DXd safety profile remained favorable compared with ICC, and no new safety signals were observed
BACKGROUND: The TROPION-Breast01 study (NCT05104866) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) with the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) versus investigator’s choice of chemotherapy (ICC) in patients with previously treated, inoperable/metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. Here we report results from the final overall survival (OS) analysis.
PATIENTS AND METHODS: Patients with inoperable/metastatic HR+/HER2- breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable, and had received 1-2 prior lines of chemotherapy in the inoperable/metastatic setting, were randomized 1:1 to Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Dual primary endpoints were PFS by BICR and OS.
RESULTS: At data cut-off, median follow-up was 22.8 months. OS for the Dato-DXd versus ICC arm did not reach statistical significance (hazard ratio, 1.01 [95% confidence interval 0.83-1.22]; P = 0.9445). Use of ADCs (trastuzumab deruxtecan and sacituzumab govitecan) as subsequent therapy was imbalanced: 12.3% in Dato-DXd arm versus 24.0% in ICC arm. Secondary efficacy endpoints (PFS by investigator assessment, objective response rate, duration of response, disease control rate at 12 weeks, time to first and second subsequent therapy or death, and time to second progression or death) continued to favor Dato-DXd at this final analysis. The overall safety profile of Dato-DXd remained favorable compared with ICC, and no new safety signals were observed with longer follow-up.
CONCLUSIONS: TROPION-Breast01 met its dual primary endpoint of PFS by BICR. While there was no statistically significant improvement in the dual primary endpoint of OS with Dato-DXd versus ICC, subsequent ADC treatment may have affected OS results. The totality of efficacy and safety data support Dato-DXd as a new treatment option for patients with previously treated, inoperable/metastatic HR+/HER2- breast cancer.
KEYWORDS: datopotamab deruxtecan, Dato-DXd, HR+ breast cancer, HER2-negative breast cancer, TROPION-Breast01, overall survival
DOI: 10.1016/j.annonc.2025.12.017