編者按：目前，最熱門的抗體與化療藥共軛物，莫過于治療HER2陽性乳腺癌的T-DM1，T即曲妥珠單抗（trastuzumab），DM1即恩坦辛（emtansine），故T-DM1不可隨意縮寫為TDM-1。此外，共軛或綴合（conjugate）是描述化合物的性質(zhì)（蛋白質(zhì)組分和非蛋白質(zhì)組分的組合），偶聯(lián)或偶合或耦合（coupling）是描述化合物之間的反應(yīng)，某些醫(yī)藥推廣資料將“共軛、綴合”物寫為“偶聯(lián)、偶合、耦合”物，似有不妥。至于“耦聯(lián)”物，則屬誤寫（具體參見全國科學(xué)技術(shù)名詞審定委員會已公布的中國規(guī)范術(shù)語）。

　　Trop-2表達于大多數(shù)三陰性乳腺癌，可能成為抗體與化療藥共軛物的潛在靶標。薩希珠單抗－戈維替康，即為抗體與化療藥共軛物，可以靶向Trop-2，選擇性遞送伊立替康的活性代謝物SN-38。

　　2017年3月14日，美國臨床腫瘤學(xué)會官方期刊《臨床腫瘤學(xué)雜志》在線發(fā)表麻省總醫(yī)院、哈佛醫(yī)學(xué)院、達納法伯癌癥研究所、范德堡英格拉姆綜合癌癥中心、科羅拉多大學(xué)、佛羅里達大學(xué)、印第安納大學(xué)、德克薩斯腫瘤醫(yī)生集團、貝勒醫(yī)學(xué)院查爾斯薩蒙斯癌癥中心、美國腫瘤醫(yī)生集團、哥倫比亞大學(xué)、康奈爾大學(xué)、海倫格雷厄姆癌癥中心、新澤西州莫里斯普萊恩斯免疫醫(yī)學(xué)的多中心單組研究，評價了薩希珠單抗－戈維替康對復(fù)發(fā)性/難治性轉(zhuǎn)移性三陰性乳腺癌患者的有效性和安全性。

　　該多中心研究入組69例自診斷后接受過中位5個（范圍：1～12）治療方案的復(fù)發(fā)性難治性轉(zhuǎn)移性三陰性乳腺癌患者，在每21天重復(fù)周期的第1、8天接受薩希珠單抗－戈維替康，起始劑量為10mg/kg。主要終點為安全性、客觀緩解率，次要終點為無進展生存、總生存。

　　結(jié)果發(fā)現(xiàn)，確認的客觀緩解率為30%（部分緩解19例，完全緩解2例），中位緩解持續(xù)時間為8.9個月（95%置信區(qū)間：6.1～11.3），臨床獲益率（完全緩解＋部分緩解＋疾病穩(wěn)定≥6個月）為46%。這些緩解發(fā)生較早，中位起效時間為1.9個月。中位無進展生存、中位總生存分別為6.0、16.6個月（95%置信區(qū)間：5.0～7.3、11.1～20.6）。

　　≥3級的不良事件包括中性粒細胞減少癥（39%）、白細胞減少癥（16%）、貧血（14%）、腹瀉（13%）；發(fā)熱性中性粒細胞減少發(fā)生率為7%。大多數(shù)（88%）存檔腫瘤標本Trop-2免疫組化為中至強陽性。未檢測到抗體與化療藥共軛物或抗體的中和抗體。

　　因此，薩希珠單抗－戈維替康具有良好的耐受性，可使轉(zhuǎn)移性三陰性乳腺癌難治性患者出現(xiàn)早期和持久緩解。Trop-2作為治療靶點和預(yù)測性生物指標，值得進一步研究。

J Clin Oncol. 2017 Mar 14. [Epub ahead of print]

Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer.

Aditya Bardia, Ingrid A. Mayer, Jennifer R. Diamond, Rebecca L. Moroose, Steven J. Isakoff, Alexander N. Starodub, Nikita C. Shah, Joyce O'Shaughnessy, Kevin Kalinsky, Michael Guarino, Vandana Abramson, Dejan Juric, Sara M. Tolaney, Jordan Berlin, Wells A. Messersmith, Allyson J. Ocean, William A. Wegener, Pius Maliakal, Robert M. Sharkey, Serengulam V. Govindan, David M. Goldenberg, Linda T. Vahdat.

Massachusetts General Hospital Cancer Center; Harvard Medical School; Dana-Farber Cancer Institute, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of Colorado Cancer Center, Aurora, CO; University of Florida Health Cancer Center, Orlando, FL; Indiana University Health Center for Cancer Care, Goshen, IN; Texas Oncology-Baylor Charles A. Sammons Cancer Center; US Oncology, Dallas, TX; Columbia University Herbert Irving Comprehensive Cancer Center; Weill Cornell Medicine, New York, NY; Helen F. Graham Cancer Center, Newark, DE; Immunomedics, Morris Plains, NJ.

PURPOSE: Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan.

PATIENTS AND METHODS: We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival.

RESULTS: In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed.

CONCLUSION: Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

DOI: 10.1200/JCO.2016.70.8297