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，对传统的内分泌治疗和HER2靶向治疗无效，转移后5年生存率仅15%。对于晚期三阴性乳腺癌，如果免疫检查点PD-L1阳性，一线治疗可以选择化疗联合免疫检查点抑制剂，但是多达60%的患者PD-L1阴性，一线治疗仍然依靠化疗。其他一线治疗选择还有多腺苷二磷酸核糖聚合酶PARP抑制剂，仅适用于少数种系BRCA基因突变患者。真实世界数据回顾分析表明，晚期三阴性乳腺癌患者大约50%未进行二线治疗，因为大约30%已经死亡。此外，对于PD-L1阳性晚期三阴性乳腺癌，如果早期术前或术后免疫检查点抑制剂治疗后复发，或者存在无法接受免疫检查点抑制剂的共存疾病，那么治疗选择仍不明确。因此，需要为晚期三阴性乳腺癌PD-L1阴性以及虽然PD-L1阳性但是不适合免疫检查点抑制剂治疗患者提供更有效的一线治疗选择。由于人类滋养层细胞表面抗原Trop-2高表达于三阴性乳腺癌，戈沙妥珠单抗由Trop-2大分子单克隆抗体沙妥珠单抗与7～8个小分子强效化疗药物戈维替康通过可水解连接分子缀合而成，靶向到达三阴性乳腺癌细胞以后，连接分子可被水解，从而释放高浓度化疗药物杀灭肿瘤。2021年，ASCENT研究首先证实，对于晚期三阴性乳腺癌至少一线治疗失败患者，戈沙妥珠单抗显著优于化疗，可显著减少进展或死亡风险。2025年5月，ASCENT-04研究再次证实，对于晚期三阴性乳腺癌一线治疗患者，免疫检查点抑制剂联合戈沙妥珠单抗显著优于联合化疗。那么，对于晚期三阴性乳腺癌不适合免疫检查点抑制剂一线治疗患者，戈沙妥珠单抗能否取代化疗？
2025年10月18日，国际四大医学期刊之一、创刊于1812年的美国麻省医学会《新英格兰医学杂志》和欧洲肿瘤内科学会第五十届大会同时发表中国工程院院士、中国医学科学院肿瘤医院徐兵河教授等30国学者共同完成的ASCENT-03研究报告，首次对三阴性乳腺癌局部晚期无法手术或已远处转移且不适合免疫检查点抑制剂患者给予戈沙妥珠单抗或化疗一线治疗的有效性和安全性进行随机分组比较。
ASCENT-03 (NCT05382299): Study of Sacituzumab Govitecan-hziy Versus Treatment of Physician's Choice in Patients With Previously Untreated Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer
Official Title: A Randomized, Open-label, Phase 3 Study of Sacituzumab Govitecan Versus Treatment of Physician's Choice in Patients With Previously Untreated, Locally Advanced, Inoperable or Metastatic Triple-Negative Breast Cancer Whose Tumors Do Not Express PD-L1 or in Patients Previously Treated With Anti-PD-(L)1 Agents in the Early Setting Whose Tumors Do Express PD-L1
该国际多中心非盲随机对照三期临床研究于2022年10月27日至2024年7月29日在30个国家229个研究中心入组晚期三阴性乳腺癌不适合免疫检查点抑制剂一线治疗患者558例，按1比1随机分为两组，其中279例给予戈沙妥珠单抗，其余279例给予紫杉醇、白蛋白紫杉醇或吉西他滨联合卡铂化疗。主要终点为无进展生存，由盲态独立中心审查委员会评定。次要终点包括总生存、客观缓解、缓解持续期和安全性。
结果，截至2025年4月2日，中位随访13.2个月，戈沙妥珠单抗组279例与化疗组279例全部入组患者相比：
中位无进展生存：9.7个月比6.9个月（95%置信区间8.1～11.1、5.6～8.2）
进展或死亡风险：减少38%（分层风险比：0.62，95%置信区间：0.50～0.77，P<0.001）
确认客观缓解率：48%比46%（95%置信区间：42～54、40～52）
中位缓解持续期：12.2个月比7.2个月（95%置信区间：9.7～13.8、5.7～8.4）
戈沙妥珠单抗组273例与化疗组269例实际用药患者相比：
≥3级不良事件发生率：66%比62%
≥3级中性粒细胞减少发生率：43%比41%
≥3级腹泻发生率：9%比1%
≥3级白细胞减少发生率：7%比13%
≥3级贫血发生率：4%比16%
任何不良事件所致停药发生率：4%比12%
因此，该研究结果表明，对于晚期三阴性乳腺癌不适合免疫检查点抑制剂一线治疗患者，戈沙妥珠单抗与化疗相比，无进展生存显著延长，进展或死亡风险减少38%，≥3级不良事件发生率相似。
相关链接
N Engl J Med. 2025 Oct 18. IF: 78.5
Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer.
Javier Cortés, Kevin Punie, Carlos Barrios, Sara A. Hurvitz, Andreas Schneeweiss, Joohyuk Sohn, Eriko Tokunaga, Adam Brufsky, Yeon Hee Park,?Binghe Xu, Roberto Hegg, Mafalda Oliveira, Alessandra Fabi, Natalya Vaksman, Theresa Valdez, Xinrui Zhang, Catherine Lai, Sara M. Tolaney; ASCENT-03 Clinical Trial Investigators.
International Breast Cancer Center, Pangaea Oncology, Quiron Group, Barcelona, Spain; Medica Scientia Innovation Research, Barcelona, Spain; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; IOB Madrid, Institute of Oncology, Hospital Beata María Ana, Madrid, Spain; Hospital Universitario TORRejón, Ribera Salud Group, Madrid, Spain; Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain; Medica Scientia Innovation Research, Ridgewood, NJ, USA; University of Washington Medicine, Fred Hutchinson Cancer Center, Seattle, USA; Hillman Cancer Center, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, USA; Gilead Sciences, Foster City, CA, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA; Oncology Center Antwerp, Ziekenhuis aan de Stroom, Antwerp, Belgium; Latin American Cooperative Oncology Group, Porto Alegre, Brazil; University of Sao Paulo, Sao Paulo, Brazil; Heidelberg University Hospital, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany; Yonsei Cancer Center, Seoul, Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan;?Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
BACKGROUND: Patients with previously untreated, locally advanced, unresectable or metastatic triple-negative breast cancer who are not candidates for inhibitors of programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) have limited treatment options.
METHODS: In this international, phase 3, open-label, randomized trial, we enrolled patients with previously untreated, advanced triple-negative breast cancer who were not candidates for PD-1 or PD-L1 inhibitors owing to previous use or coexisting conditions. Patients had either PD-L1-negative tumors with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages divided by the total number of viable tumor cells, multiplied by 100) of less than 10 or PD-L1-positive tumors with a CPS of 10 or higher and were assigned in a 1:1 ratio to receive sacituzumab govitecan or chemotherapy (paclitaxel, nanoparticle albumin-bound paclitaxel, or gemcitabine plus carboplatin). The primary end point was progression-free survival, assessed by blinded independent central review. Secondary end points included overall survival, objective response, the duration of response, and safety.
RESULTS: Among 558 patients, median progression-free survival was 9.7 months (95% confidence interval [CI], 8.1 to 11.1) with sacituzumab govitecan and 6.9 months (95% CI, 5.6 to 8.2) with chemotherapy (stratified hazard ratio for disease progression or death, 0.62; 95% CI, 0.50 to 0.77; P<0.001). An objective response was confirmed in 48% of patients (95% CI, 42 to 54) who received sacituzumab govitecan and 46% (95% CI, 40 to 52) who received chemotherapy; the median response duration was 12.2 months (95% CI, 9.7 to 13.8) and 7.2 months (95% CI, 5.7 to 8.4), respectively. Adverse events of grade 3 or higher occurred in 66% of patients who received sacituzumab govitecan (most frequently neutropenia [in 43%], diarrhea [in 9%], and leukopenia [in 7%]) and in 62% of patients who received chemotherapy (most frequently neutropenia [in 41%], anemia [in 16%], and leukopenia [in 13%]). The incidence of adverse events that led to discontinuation of sacituzumab govitecan or at least one chemotherapy drug was 4% and 12%, respectively.
CONCLUSIONS: Sacituzumab govitecan led to significantly longer progression-free survival than chemotherapy among patients with advanced triple-negative breast cancer who were not candidates for treatment with PD-1 or PD-L1 inhibitors. The incidence of adverse events of grade 3 or higher with sacituzumab govitecan was similar to that with chemotherapy, but adverse events were common.
Funded by?Gilead Sciences
ASCENT-03 ClinicalTrials.gov number: NCT05382299
DOI: 10.1056/NEJMoa2511734
