三阴性乳腺癌新药再次登顶新英格兰
三阴性乳腺癌的雌激素受体、孕激素受体、HER2均为阴性，故对内分泌治疗和HER2靶向治疗无效，晚期主要依靠化疗。沙西妥珠单抗戈维替康是人类滋养层细胞表面抗原TROP2（又称肿瘤相关钙信号转导蛋白）人源化单克隆抗体沙西妥珠单抗与化疗药拓扑异构酶抑制剂伊立替康活性代谢产物戈维替康由可水解的连接分子缀合而成，每个沙西妥珠单抗分子平均可缀合7.6个戈维替康分子。由于戈维替康的毒性太强，无法直接单独用于患者，沙西妥珠单抗能够将戈维替康靶向传输至癌细胞，随后连接分子被癌细胞水解，从而在癌细胞内释放出高浓度的戈维替康杀灭肿瘤。2019年，美国麻省医学会《新英格兰医学杂志》发表的一期和二期临床研究结果初步表明，对于既往多次治疗失败的晚期三阴性乳腺癌患者，沙西妥珠单抗戈维替康的客观缓解率可达34.3%，主要不良反应为贫血和中性粒细胞减少，不良反应所致停药患者较少。2020年，美国批准沙西妥珠单抗戈维替康成为首个用于三阴性乳腺癌的抗体化疗药缀合物（又称偶联物）。
2021年4月22日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》发表哈佛大学麻省总医院癌症中心、达纳法伯癌症研究所、洛杉矶加利福尼亚大学、琼森综合癌症中心、匹兹堡大学医学中心马吉妇女医院希尔曼癌症中心、俄亥俄州立大学韦克斯纳医学中心、哥伦比亚大学欧文医学中心、纽约纪念医院斯隆凯特林癌症中心、亚特兰大北区医院、佛罗里达肿瘤医院、乔治城大学伦巴第综合癌症中心、洛矶山癌症中心、贝勒大学医学中心德克萨斯肿瘤医院、北卡罗来纳大学莱恩伯格综合癌症中心、旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、法国巴黎文理研究大学居里学院、图卢兹大学癌症研究所、尤金马奎斯癌症中心、比利时鲁汶大学医院、布鲁塞尔自由大学朱尔博代研究所、西班牙巴塞罗纳大学医院肿瘤研究所、奎隆国际乳腺癌中心、加拿大蒙特利尔大学犹太综合医院西格尔癌症中心、英国伦敦大学玛丽王后学院巴茨癌症研究所、意大利米兰詹尼博纳东纳基金会、德国法兰克福伯达尼医院的ASCENT三期临床研究报告，进一步比较了沙西妥珠单抗戈维替康或单药化疗对难治型晚期三阴性乳腺癌患者的有效性和安全性。
ASCENT (NCT02574455): Phase III Study of Sacituzumab Govitecan (IMMU-132) in Refractory/Relapsed Triple-Negative Breast Cancer (IMMU-132-05)
该国际多中心非盲随机对照三期临床研究于2017年11月～2019年9月从7个国家88家医院入组复发或治疗失败的晚期三阴性乳腺癌未脑转移患者468例（中位年龄54岁、都经过紫杉类化疗）随机分为两组，其中235例给予沙西妥珠单抗戈维替康、其余233例由医师选择单药化疗（艾立布林、长春瑞滨、卡培他滨、吉西他滨）。该研究主要终点为未脑转移患者的无进展生存（由盲法独立集中复核确定），次要终点包括总生存、客观缓解率、安全性。
结果，沙西妥珠单抗戈维替康与化疗相比：
进展或死亡事件：166例比150例
中位无进展生存：5.6月比1.7月（95%置信区间：4.3～6.3、1.5～2.6）
进展或死亡风险：减少59%（风险比：0.41，95%置信区间：0.32～0.52，P<0.001）
中位总生存时间：12.1月比6.7个月（95%置信区间：10.7～14.0、5.8～7.7）
总死亡风险：减少52%（风险比：0.48，95%置信区间：0.38～0.59，P<0.001）
客观缓解率：35%比5%
亚组分析表明，无论年龄、种族、既往治疗方案数量、地理区域、是否用过PD-1或PD-L1抑制剂、有无肝转移，沙西妥珠单抗戈维替康的进展或死亡风险都显著减少。
沙西妥珠单抗戈维替康与化疗相比，≥3级治疗相关主要不良事件发生率：
中性粒细胞减少：51%比33%
白细胞减少：10%比5%
腹泻：10%比<1%
贫血：8%比5%
发热性中性粒细胞减少：6%比2%
不良事件所致死亡：3例（与沙西妥珠单抗戈维替康治疗无关）比3例
因此，该研究结果表明，对于晚期三阴性乳腺癌患者，沙西妥珠单抗戈维替康与单药化疗相比，无进展生存和总生存显著较长，骨髓抑制和腹泻发生率较高。
据悉，沙西妥珠单抗戈维替康由美国吉利德旗下免疫组学研发，云顶新耀已于2020年获得中国国家药品监督管理局批准开展三阴性乳腺癌二期注册临床研究，预计将于2021年10月31日初步完成。
相关链接
该研究第一作者、哈佛大学麻省总医院Aditya Bardia
该研究第二作者、达纳法伯癌症研究所Sara A. Hurvitz
该研究第三作者、加州大学洛杉矶分校Sara M. Tolaney
N Engl J Med. 2021 Apr 22;384(16):1529-1541.
Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.
Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators.
Massachusetts General Hospital Cancer Center, Dana-Farber Cancer Institute, Boston; University of California, Los Angeles; Jonsson Comprehensive Cancer Center, Los Angeles; Institut Curie, Paris, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse; Centre Eugène Marquis, Rennes, France; University Hospitals Leuven, Leuven; Institut Jules Bordet-Université Libre de Bruxelles, Brussels, Belgium; Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology; International Breast Cancer Center, Quiron Group, Barcelona; Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh; Ohio State University Wexner Medical Center, Columbus; Columbia University Irving Medical Center; Memorial Sloan Kettering Cancer Center, New York; Northside Hospital, Atlanta; Florida Cancer Specialists, Tampa; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Rocky Mountain Cancer Centers, Greenwood Village, CO; Baylor University Medical Center and Texas Oncology, Dallas; Segal Cancer Centre, Jewish General Hospital, Montreal; Barts Cancer Institute, Queen Mary University of London, London; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill; Gianni Bonadonna Foundation, Milan; Hamatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany; Immunomedics, Morris Plains, NJ; University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.
BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.
METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.
RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.
CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan.
Funded by Immunomedics
ASCENT ClinicalTrials.gov number: NCT02574455; EudraCT number: 2017-003019-21
PMID: 33882206
DOI: 10.1056/NEJMoa2028485