三陰性乳腺癌的雌激素受體、孕激素受體、人類表皮生長因子受體HER2均為陰性，對傳統(tǒng)的內(nèi)分泌治療和HER2靶向治療無效，轉(zhuǎn)移后5年生存率僅15%。對于晚期三陰性乳腺癌，如果免疫檢查點PD-L1陽性，一線治療可以選擇化療聯(lián)合免疫檢查點抑制劑，但是多達60%的患者PD-L1陰性，一線治療仍然依靠化療。其他一線治療選擇還有多腺苷二磷酸核糖聚合酶PARP抑制劑，僅適用于少數(shù)種系BRCA基因突變患者。真實世界數(shù)據(jù)回顧分析表明，晚期三陰性乳腺癌患者大約50%未進行二線治療，因為大約30%已經(jīng)死亡。此外，對于PD-L1陽性晚期三陰性乳腺癌，如果早期術(shù)前或術(shù)后免疫檢查點抑制劑治療后復(fù)發(fā)，或者存在無法接受免疫檢查點抑制劑的共存疾病，那么治療選擇仍不明確。因此，需要為晚期三陰性乳腺癌PD-L1陰性以及雖然PD-L1陽性但是不適合免疫檢查點抑制劑治療患者提供更有效的一線治療選擇。由于人類滋養(yǎng)層細胞表面抗原Trop-2高表達于三陰性乳腺癌，戈沙妥珠單抗由Trop-2大分子單克隆抗體沙妥珠單抗與7～8個小分子強效化療藥物戈維替康通過可水解連接分子綴合而成，靶向到達三陰性乳腺癌細胞以后，連接分子可被水解，從而釋放高濃度化療藥物殺滅腫瘤。2021年，ASCENT研究首先證實，對于晚期三陰性乳腺癌至少一線治療失敗患者，戈沙妥珠單抗顯著優(yōu)于化療，可顯著減少進展或死亡風(fēng)險。2025年5月，ASCENT-04研究再次證實，對于晚期三陰性乳腺癌一線治療患者，免疫檢查點抑制劑聯(lián)合戈沙妥珠單抗顯著優(yōu)于聯(lián)合化療。那么，對于晚期三陰性乳腺癌不適合免疫檢查點抑制劑一線治療患者，戈沙妥珠單抗能否取代化療？

　　2025年10月18日，國際四大醫(yī)學(xué)期刊之一、創(chuàng)刊于1812年的美國麻省醫(yī)學(xué)會《新英格蘭醫(yī)學(xué)雜志》和歐洲腫瘤內(nèi)科學(xué)會第五十屆大會同時發(fā)表中國工程院院士、中國醫(yī)學(xué)科學(xué)院腫瘤醫(yī)院徐兵河教授等30國學(xué)者共同完成的ASCENT-03研究報告，首次對三陰性乳腺癌局部晚期無法手術(shù)或已遠處轉(zhuǎn)移且不適合免疫檢查點抑制劑患者給予戈沙妥珠單抗或化療一線治療的有效性和安全性進行隨機分組比較。

• 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

　　該國際多中心非盲隨機對照三期臨床研究于2022年10月27日至2024年7月29日在30個國家229個研究中心入組晚期三陰性乳腺癌不適合免疫檢查點抑制劑一線治療患者558例，按1比1隨機分為兩組，其中279例給予戈沙妥珠單抗，其余279例給予紫杉醇、白蛋白紫杉醇或吉西他濱聯(lián)合卡鉑化療。主要終點為無進展生存，由盲態(tài)獨立中心審查委員會評定。次要終點包括總生存、客觀緩解、緩解持續(xù)期和安全性。

　　結(jié)果，截至2025年4月2日，中位隨訪13.2個月，戈沙妥珠單抗組279例與化療組279例全部入組患者相比：

• 中位無進展生存：9.7個月比6.9個月（95%置信區(qū)間8.1～11.1、5.6～8.2）

• 進展或死亡風(fēng)險：減少38%（分層風(fēng)險比：0.62，95%置信區(qū)間：0.50～0.77，P<0.001）

• 確認客觀緩解率：48%比46%（95%置信區(qū)間：42～54、40～52）

• 中位緩解持續(xù)期：12.2個月比7.2個月（95%置信區(qū)間：9.7～13.8、5.7～8.4）

　　戈沙妥珠單抗組273例與化療組269例實際用藥患者相比：

• ≥3級不良事件發(fā)生率：66%比62%

• ≥3級中性粒細胞減少發(fā)生率：43%比41%

• ≥3級腹瀉發(fā)生率：9%比1%

• ≥3級白細胞減少發(fā)生率：7%比13%

• ≥3級貧血發(fā)生率：4%比16%

• 任何不良事件所致停藥發(fā)生率：4%比12%

　　因此，該研究結(jié)果表明，對于晚期三陰性乳腺癌不適合免疫檢查點抑制劑一線治療患者，戈沙妥珠單抗與化療相比，無進展生存顯著延長，進展或死亡風(fēng)險減少38%，≥3級不良事件發(fā)生率相似。

相關(guān)鏈接

• 三陰性乳腺癌新藥再登新英格蘭

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