Trop-2 ADC强势布局TNBC，TROPION-Breast02即将揭幕晚期一线治疗

摘要：三阴性乳腺癌（TNBC）既往因缺乏广泛存在的治疗靶点难以从精准治疗中获益，是当前预后最差的乳腺癌亚型。随着近年来对Trop-2靶点认识的加深，靶向Trop-2的抗体偶联药物（ADC）在TNBC治疗中取得了长足进步。以德达博妥单抗（Dato-DXd）为代表的新一

编者按：三阴性乳腺癌（TNBC）既往因缺乏广泛存在的治疗靶点难以从精准治疗中获益，是当前预后最差的乳腺癌亚型。随着近年来对Trop-2靶点认识的加深，靶向Trop-2的抗体偶联药物（ADC）在TNBC治疗中取得了长足进步。以德达博妥单抗（Dato-DXd）为代表的新一代Trop-2 ADC已经从晚期到早期全面布局TNBC，在I/II期临床研究不断突破的基础上，正在向III期深入拓展，为临床带来了新的选择。在即将召开的2025年欧洲肿瘤内科学会年会（ESMO）上，Dato-DXd一线治疗TNBC的III期TROPION-Breast02研究（LBA21）将以最新突破性摘要（LBA）形式披露，展现Dato-DXd较传统化疗在无进展生存期（PFS）和总生存期（OS）的双重获益，将揭幕晚期一线治疗新篇章。

Trop-2 ADC开启TNBC精准治疗新篇章

乳腺癌是全球女性第一大恶性肿瘤，其中TNBC约占15%-20%[1]，是当前乳腺癌中预后最差的一种亚型，具有分化差、侵袭性强、更早且更易发生转移的特点。约1/3的TNBC患者会出现复发或远处转移[2]，5年生存率不足15%，显著低于乳腺癌整体31%的5年生存率[3,4]。既往TNBC缺乏有效的治疗靶点，而PD-L1阳性、gBRCA1/2突变、HER2低表达等人群在TNBC患者中占比较小，故晚期TNBC一般以化疗作为标准治疗方案，预后不够理想。

Trop-2靶点的发现为TNBC精准开启新的篇章，该靶点在96%的TNBC患者中存在高表达，推动了针对该靶点的ADC药物开发[5]。近年来，已有德达博妥单抗（Dato-DXd）、芦康沙妥珠单抗（SKB264）、戈沙妥珠单抗（SG）等靶向Trop-2 ADC在TNBC展开相关探索或获批适应症，为TNBC精准治疗打开了局面。

Dato-DXd药物结构

Dato-DXd作为新型的Trop-2 ADC，采用了第一三共专有的DXd ADC平台设计，在分子结构及作用机制层面进行了优化。其靶向Trop-2部分为人源化抗Trop-2 IgG1单克隆抗体MAAP-9001a，作为ADC药物的骨架，每个抗体的连接药物的平均药物抗体比（DAR）为4，相比较高DAR可最大化治疗窗并限制药物毒性。其细胞毒载荷为拓扑异构酶I抑制剂DXd，抗肿瘤活性约为SN38的10倍，与乳腺癌常见药物的作用机制并不重叠，抗肿瘤活性强且无交叉耐药反应。其连接子为可裂解GGFG四肽连接子，在血液中可以维持高度稳定性，进入肿瘤细胞后被特异性酶选择性剪切，尽可能地降低了载药的提前释放，保证了安全性。裂解后释放的DXd具有较高的细胞膜渗透性，可通过旁观者效应，进一步提升抗肿瘤效果。Dato-DXd优化的分子结构及作用机制构筑了疗效与安全性双优基石，改进了药代动力学特征，成为了当前唯一21天给药1次的Trop-2 ADC，临床应用更加便捷，更令人期待。

从晚期到早期，全面布局TNBC

Dato-DXd在乳腺癌领域展现了巨大的潜力，正在全面布局TNBC领域。在后线治疗方面，I期TROPION-PanTumor01研究纳入了44例既往中位治疗3线后进展的晚期TNBC患者，使用Dato-DXd单药治疗的客观缓解率（ORR）为31.8%，中位无进展生存期（PFS）为4.4个月，中位总生存期（OS）为14.3个月，最常见的治疗期间不良事件（TEAE）为口腔炎，未见间质性肺病（ILD）[6]。

TROPION-PanTumor01研究TNBC队列PFS

I/II期TROPION-PanTumor02研究主要针对中国实体瘤患者，纳入79例既往至少接受2种化疗方案治疗晚期疾病的TNBC患者。Dato-DXd治疗所取得的确认ORR为33.8%，mPFS为5.3个月，mOS为13.5个月，最常见的TEAE为口腔炎和恶心，且多为低级别，仅1例出现2级ILD，总体表现与国际研究表现一致[7]。

TROPION-PanTumor02研究TNBC患者PFS与OS

在一线治疗方面，Ib/II期BEGONIA研究纳入62例不可切除的晚期或转移性TNBC患者，使用Dato-DXd联合度伐利尤单抗一线治疗，ORR达79%，mPFS为13.8个月，常见TEAE为口腔炎和恶心，3例患者出现ILD，均为1-2级，奠定了一线治疗基础[8]。

在早期TNBC新辅助治疗方面，II期I-SPY2.2研究将Dato-DXd联合度伐利尤单抗作为序贯疗法（A区）的首要环节，并根据实际情况采用不同的化疗方案（B/C区）。该研究A区纳入106例患者，其中TNBC患者共63例。TNBC人群的完全病理缓解率（pCR）为62%，其中54%仅通过Dato-DXd联合度伐利尤单抗（A区）实现pCR，92.3%可通过A区序贯B区实现pCR，主要不良事件同样为口腔炎和恶心，所有患者中仅3例出现ILD，均为1-2级，为早期应用开辟了方向[9]。

此外，在乳腺癌脑转移方面，II期TUXEDO-2研究主要针对新诊断的未经治或经治后进展的伴脑转移TNBC患者，均无立即局部治疗指征。截至2022年2月7日已入组8例患者，其中6例为初治患者，使用Dato-DXd治疗后，颅内缓解率（RR）为37.5%（3/8），mPFS为4.2个月，未观察到新的安全性信号，为活动性脑转移的TNBC患者提供了新的系统治疗机会[10]。

TROPION-Breast02研究ESMO披露，书写一线治疗新方案

在从晚期到早期全面布局的基础上，Dato-DXd将继续深入验证其在TNBC的治疗效果。III期TROPION-Breast05研究则将探讨Dato-DXd±度伐利尤单抗对比化疗用于PD-L1阳性晚期TNBC患者一线治疗可行性[11]。III期TROPION-Breast03研究正在探索Dato-DXd±度伐利尤单抗用于II-III期TNBC新辅助治疗后non-pCR患者强化辅助治疗效果[12]。III期TROPION-Breast03研究使用Dato-DXd±度伐利尤单抗新辅助治疗TNBC以及HR低表达/HER2阴性乳腺癌患者[13]。一系列III期临床研究正在全面、深入开发TNBC治疗领域，令人倍加期待。

2025年10月19日09:25-09:35，TROPION-Breast02研究公布

2025年10月19日，在ESMO年会转移性乳腺癌专场，Dato-DXd一线治疗TNBC的III期TROPION-Breast02研究（LBA21）将以LBA形式首次披露，为临床带来全新的一线Trop-2 ADC方案[14]。该研究是一项III期、随机化、开放标签、国际多中心研究，主要纳入无法接受PD-1/PD-L1抑制剂治疗的、既往未接受化疗或其他系统性抗癌治疗的转移性或局部复发的不可手术TNBC患者。患者按照1:1随机分为Dato-DXd组和研究者选择的化疗组（ICC：含紫杉醇、白蛋白结合型紫杉醇、卡培他滨、艾立布林或卡铂）。主要研究终点为BICR评估的PFS和OS，次要终点包括研究者评估的PFS、ORR、DoR、DCR、PROs、安全性等，并根据Trop-2、PD-L1设置探索性终点。

TROPION-Breast02研究设计

目前已披露的信息显示，该研究中Dato-DXd较化疗在不适合免疫治疗的晚期TNBC患者一线治疗中取得了OS和PFS的显著获益，安全性特征也与既往研究表现一致，将改写TNBC一线治疗格局。值得一提的是，TROPION-Breast02研究纳入了快速复发疾病人群（DFI小于6个月），在包含这部分因侵袭性高、预后差而常常被排除在III期临床研究之外的人群基础上，该研究仍取得OS阳性结果，使其在ESMO年会披露的完整数据更加值得期待。截至目前已公布的信息，TROPION-Breast02研究是在不适合免疫治疗的晚期TNBC人群一线治疗中首个取得OS获益的III期研究，为此类亟需新型治疗方案的患者正式揭开了一线ADC治疗新时代的序幕[15]。

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