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2016年6月3日，美国临床肿瘤学会（ASCO）2016年会在美国芝加哥盛大召开，当地时间下午1点，在“传统治疗新进展”重要研究新闻发布会上，ASCO公布了LBA509研究——抗体偶联药物Sacituzumabgovitecan治疗复发或难治性三阴乳腺癌（mTNBC）的疗效和安全性。
抗体“弹头”携带化疗药直击肿瘤细胞
Sacituzumabgovitecan（IMMU-132）是一种抗体偶联药物（Antibody Drug Conjugate,ADC），通过蛋白链接技术将「单克隆抗体RS7」和「依立替康的活性代谢产物SN-38」连接在一起。RS7靶向人滋养细胞表面抗原Trop-2，该抗原在超过80%的三阴性乳腺癌中大量表达。RS7携带SN-38，选择性结合乳腺癌细胞的Trop-2，进入细胞后释放SN-38，发挥细胞毒作用。IMMU-132的这种作用机制理论上能够增加肿瘤内的药物浓度，同时减少正常组织的毒性。
抗Trop-2抗体RS7有一定间接抗肿瘤活性，可以激活免疫反应杀伤肿瘤细胞。因此IMMU-132在提供细胞毒效应的同时，还具有潜在免疫抗肿瘤效应。
主要研究内容
IMMU-132治疗mTNBC是单臂、开放标签Ⅰ/Ⅱ期临床试验的一部分，由于Trop-2在多种上皮类肿瘤中表达，因此这项评估IMMU-132疗效和安全性的临床试验纳入了多个瘤种。
该研究动态入组乳腺癌患者已超过80名，治疗周期21天，第1天和第8天接受IMMU-132静脉注射，治疗一直持续直到疾病进展或无法耐受。
结果
2016年4月的初步分析显示，大多数患者免疫组化检查Trop-2表达2+或3+。
◆所有入组乳腺癌患者中，有62名患者曾接受至少2种治疗，该群患者中位无进展生存（PFS）为5.6个月，中位总生存（OS）为14.3个月。
◆研究中60%患者仍存活，约33%的患者肿瘤缩小30%以上，2例达到完全缓解。
◆对于出现客观缓解的患者，中位至疾病进展时间为12.6个月。
◆最常见的不良反应是血细胞计数下降和腹泻，无患者因药物毒性停止治疗。
结语
Trop-2靶向ADC药物IMMU-132在其他治疗无效、复发/难治性、转移三阴乳腺癌中表现出良好、持续的肿瘤缓解，毒性可控。疾病缓解时间延长很有可能是IMMU-132诱导的免疫抗肿瘤反应在起作用。
IMMU-132在2016年2月已经获得美国FDA的突破性疗法认定，将大大加速其在mTNBC中的应用进度。未来研究者们计划进行更大规模的国际Ⅲ期临床试验，目标对象是经过至少两种治疗无效的mTNBC患者，或许能够改变此类乳腺癌临床束手无策的困难处境。
会议专题》》》2016年ASCO年会专题报道
摘要阅读
Abstract No:LBA509
Therapyof relapsed/refractory metastatic triple-negative breast cancer (mTNBC) with ananti-Trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan(IMMU-132): Phase II results
Session: Future Directions inBreast Cancer Treatment: New Drugs, New Markers
Type: Clinical Science Symposium
Author(s): Aditya Bardia, JenniferRobinson Diamond, Wells A. Messersmith,et al.
Background: Pts with mTNBC have anaggressive course with limited effective therapy options. Sacituzumab govitecan(IMMU-132) is a novel ADC comprising SN-38, the active metabolite of thetopoisomerase inhibitor, irinotecan, conjugated to an anti-Trop-2 humanizedmAb. The mAb and ADC show immunotherapy effects in vitro (ADCC). Trop-2'sexpression is increased in most epithelial cancers (>80%), including TNBC.
Methods: A Phase I/II clinicaltrial (ClinicalTrials.gov, NCT01631552) enrolled relapsed/refractive (R/R) ptswith mTNBC dosed with intravenous IMMU-132 on days 1 and 8 of 21-day treatmentcycles. Treatment continued based on tolerance or until progression. Results,including complete responses (CR), partial response (PR), stable disease (SD),and clinical benefit ratio (CBR6), from the phase II are given.
Results: A total of 80 pts (66 at10 mg/kg) with R/R mTNBC have been treated, including a subset of 49post-taxane, at least 3rd line pts, with a median of 3 prior therapiesadministered in the metastatic setting (range, 2-10) and treated at 10 mg/kg. Amajority of patients had tumors with Trop-2 2+/3+ tumor expression by immunohistochemistry,suggestive of increased expression in TNBC. As of Jan 25, 2016, objective tumorresponse rate (n=49), defined as CR (one pt) + PR (16 pts) = 35%, including 88%responses confirmed by RECIST 1.1. The responses were prolonged with medianduration of response estimated to be 10.8 mos by Kaplan Meier, suggesting alsoa potential immunotherapy effect. The CBR6 (CR+PR+SD>6 months) = 45%.Current median PFS = 5.7 mos (73% maturity), and median overall survival is notyet reached, with 69% pts still alive at 28 mos after enrollment of first pt.Among current adverse events in the 10 mg/kg dosing group, g rade ≥3 drug-related toxicities includedneutropenia (23%), diarrhea (8.5%), anemia (6%), and leukopenia (6%). No ptdeveloped antibodies (by ELISA) to the antibody or drug.
Conclusions: The Trop-2-targetingADC, IMMU-132, delivering cytotoxic doses of SN-38, shows high objective anddurable tumor responses with manageable toxicity in heavily pretreated pts withR/R mTNBC.
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