三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体II（HER2）均为阴性，对激素疗法和HER2靶向疗法无效，目前全身治疗标准仍以化疗为主。对于既往治疗失败的转移性三阴性乳腺癌患者，标准化疗的缓解率较低、无病生存较短。
2019年2月21日，美国麻省医学会《新英格兰医学杂志》正式发表哈佛大学、麻省总医院、达纳法伯癌症研究所、范德堡大学、康奈尔大学、纽约长老会医院、哥伦比亚大学、科罗拉多大学、贝勒大学、佛罗里达大学、耶鲁大学、旧金山加利福尼亚大学的I/II期临床研究报告，探讨了沙西妥珠单抗戈维替康对于难治型转移性三阴性乳腺癌的有效性和安全性。
沙西妥珠单抗戈维替康（IMMU-132）是人类滋养层细胞表面抗原II（Trop-2，又称肿瘤相关钙信号转导蛋白II或上皮糖蛋白I）人源化单克隆抗体沙西妥珠单抗（hRS7 IgG1κ）与化疗药伊立替康活性代谢产物戈维替康（SN-38）的可分解结合物，能够将高浓度的SN-38靶向传输至肿瘤。
该多中心单组I/II期研究于2013年6月～2017年2月入组既往抗癌治疗失败≥2次（中位3次，范围2～10次）的转移性三阴性乳腺上皮晚期癌患者108例，每21天的第1天和第8天静脉注射剂量为每公斤体重10毫克的沙西妥珠单抗戈维替康，直至疾病进展或毒性反应无法耐受。研究终点包括安全性、当地根据实体肿瘤缓解评价标准（RECIST）1.1版评定的客观缓解率、缓解持续时间、临床获益率（定义为完全或部分缓解或疾病稳定至少6个月）、无进展生存、总生存。事后分析通过盲法独立集中复核对缓解率和持续时间进行评定。
结果，当地评定完全缓解3例、部分缓解33例，客观缓解率为33.3%（95%置信区间：24.6～43.1），缓解持续时间中位7.7个月（95%置信区间：4.9～10.8），临床获益率为45.4%（95%置信区间：35.8～55.2）。
通过盲法独立集中复核进行评定，客观缓解率34.3%（95%置信区间：25.4～44.0），缓解持续时间中位9.1个月（95%置信区间：4.6～11.3）。
无进展生存中位5.5个月（95%置信区间：4.1～6.3），总生存中位13.0个月（95%置信区间：11.2～13.7）。
治疗期间死亡患者4例，由于不良事件停止治疗患者3例（2.8%）。
发生率≥10%的3～4级不良事件包括贫血和中性粒细胞减少；发热性中性粒细胞减少患者10例（9.3%）。
因此，该研究结果表明，对于既往多次治疗失败的转移性三阴性乳腺癌患者，沙西妥珠单抗戈维替康仍可获得超过33%的客观缓解，主要不良反应为血液毒性，由于不良反应停止治疗的患者较少。
N Engl J Med. 2019 Feb 21;380(8):741-751.
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer.
Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O'Shaughnessy J, Moroose RL, Santin AD, Abramson VG, Shah NC, Rugo HS, Goldenberg DM, Sweidan AM, Iannone R, Washkowitz S, Sharkey RM, Wegener WA, Kalinsky K.
Massachusetts General Hospital Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston; Vanderbilt-Ingram Cancer Center, Nashville; Weill Cornell Medical College, New York-Presbyterian-Columbia University Irving Medical Center, New York; University of Colorado Cancer Center, Aurora; Texas Oncology, Baylor University Medical Center, US Oncology, Dallas; Orlando Health University of Florida Health Cancer Center, Orlando; Yale University School of Medicine, New Haven, CT; University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco; Immunomedics, Morris Plains, NJ; AIS Consulting, Ann Arbor, MI.
BACKGROUND: Standard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.
METHODS: We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review.
RESULTS: The 108 patients with triple-negative breast cancer had received a median of 3 previous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7).
CONCLUSIONS: Sacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions.
Funded by Immunomedics
IMMU-132-01 ClinicalTrials.gov number: NCT01631552
PMID: 30786188
DOI: 10.1056/NEJMoa1814213
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