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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HER2均为阴性，对内分泌治疗和传统HER2靶向治疗基本无效，失去手术和放疗等局部治疗机会的晚期患者主要依靠全身化疗。随着抗体缀合药物的问世，可将靶点抗体与化疗药物的优势合二为一，使晚期三阴性乳腺癌化疗上升到靶向化疗的新维度。2019年《新英格兰医学杂志》发表初步研究证实全球首款滋养层细胞表面抗原Trop-2抗体缀合药物戈沙妥珠单抗对晚期三阴性乳腺癌有效。2021年《新英格兰医学杂志》首次发表升维（ASCENT）研究报告，证实戈沙妥珠单抗与医师选择单药化疗相比，可显著延长晚期三阴性乳腺癌患者的无进展生存和总生存，成为目前全球唯一获批用于三阴性乳腺癌的抗体缀合药物。2023年《欧洲癌症杂志》再次发表ASCENT研究报告，进一步证实戈沙妥珠单抗还可显著改善患者健康生活质量。 ASCENT/IMMU-132-05 (NCT02574455): Trial of Sacituzumab Govitecan in Participants With Refractory/Relapsed Metastatic Triple-Negative Breast Cancer (An International, Multi-Center, Open-Label, Randomized, Phase III Trial of Sacituzumab Govitecan Versus Treatment of Physician Choice in Patients With Metastatic Triple-Negative Breast Cancer Who Received at Least Two Prior Treatments)相关链接 2024年2月29日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表美国吉利德科学、哈佛大学医学院、麻省总医院癌症中心、达纳法伯癌症研究院、旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、匹兹堡大学医学中心马吉妇女医院希尔曼癌症中心、埃默里大学温希普癌症研究所、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、华盛顿大学医学院弗雷德哈钦森癌症中心、法国巴黎大学居里研究院、尤金马奎斯癌症中心、比利时鲁汶大学医院癌症研究所、布鲁塞尔自由大学朱尔博代研究院、西班牙巴塞罗那大学希伯伦谷医院肿瘤研究所、巴塞罗那国际乳腺癌中心、意大利贾尼博纳多纳基金会、德国法兰克福贝塔尼医院的ASCENT研究最终分析报告，报告了最终疗效终点分析和按TROP2表达和HER2状态分层的事后分析结果，并提供了安全分析更新。 该国际多中心非盲随机对照三期临床研究入组复发或治疗失败的晚期三阴性乳腺癌患者529例随机分为两组：其中267例给予戈沙妥珠单抗，其余262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），直至疾病进展或毒性反应无法耐受。主要终点为无进展生存，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、临床获益率和安全性。 结果，戈沙妥珠单抗与医师选择单药化疗相比： 中位随访时间：11.2个月比6.3个月（范围：0.3～30.8、0～29.4） 中位无进展生存：4.8个月比1.7个月 进展或死亡风险：减少59%（风险比：0.41，95%置信区间：0.33～0.52） 中位总生存：11.8个月比6.9个月 总死亡风险：减少49%（风险比：0.51，95%置信区间：0.42～0.63） 客观缓解率：31%比4%（比值比：11.0，P<0.0001） 临床获益率：40%比8%（比值比：8.1，P<0.0001）
将168例患者按Trop-2表达水平测定结果四等分为四组，各组戈沙妥珠单抗与医师选择单药化疗相比，无进展生存都显著改善，总生存有改善趋势。 无论HER2零表达还是低表达，戈沙妥珠单抗与医师选择单药化疗相比，无进展生存、总生存都显著改善。无论HER2零表达还是低表达，Trop-2都高表达。 总体而言，戈沙妥珠单抗的安全性可控，不良事件所致治疗相关停药比例≤5%，并且没有治疗相关死亡。全部亚组的安全性都一致。 因此，该研究最终分析结果证实，戈沙妥珠单抗与化疗相比，晚期三阴性乳腺癌患者显著获益，进一步肯定戈沙妥珠单抗可以作为晚期三阴性乳腺癌至少一线治疗后患者的有效治疗选择。 J Clin Oncol. 2024 Feb 29. IF: 45.3 Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. OPEN ACCESS Bardia A, Rugo HS, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Kalinsky K, Cortés J, Shaughnessy JO, Diéras V, Carey LA, Gianni L, Piccart-Gebhart M, Loibl S, Yoon OK, Pan Y, Hofsess S, Phan SC, Hurvitz SA. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Institut Curie, Paris, France; Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA; Winship Cancer Institute, Emory University, Atlanta, GA; International Breast Cancer Center, Quiron Group, Barcelona, Spain; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX; Centre Eugène Marquis, Rennes, France; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Gianni Bonadonna Foundation, Milan, Italy; Institut Jules Bordet and l'Université Libre de Bruxelles, Brussels, Belgium; Hamatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany; Gilead Sciences, Inc, Foster City, CA; Gilead Sciences, Inc, Morris Plains, NJ; UW Medicine, Fred Hutchinson Cancer Center, Seattle, WA. Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study. Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided. In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups. These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later. TRIAL REGISTRATION: ClinicalTrials.gov NCT02574455 PMID: 38422473 DOI: 10.1200/JCO.23.01409
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