13年前，CLEOPATRA研究确立紫杉类＋曲妥珠单抗＋帕妥珠单抗三药联合一线治疗HER2阳性晚期乳腺癌的标准方案地位。4年前，DESTINY-Breast03研究确立德曲妥珠单抗单药二线治疗HER2阳性晚期乳腺癌的标准方案地位。那么，德曲妥珠单抗±帕妥珠单抗能否取代紫杉类＋曲妥珠单抗＋帕妥珠单抗三药联合成为HER2阳性晚期乳腺癌一线治疗标准方案地位？
2025年10月29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》在线发表美国哈佛大学医学院达纳法伯癌症研究院萨拉·托拉尼、中国人民解放军总医院第五医学中心江泽飞、哈尔滨医科大学附属肿瘤医院张清媛等20位学者的DESTINY-Breast09研究报告，首次对德曲妥珠单抗±帕妥珠单抗与紫杉类＋曲妥珠单抗＋帕妥珠单抗三药联合一线治疗HER2阳性晚期乳腺癌的有效性和安全性进行随机分组头对头直接比较。
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DESTINY-Breast09 (NCT04784715): TRAStuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, TRAStuzumab and Pertuzumab in HER2-positive Metastatic Breast Cancer
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Official Title: Phase III Study of Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive, First-line Metastatic Breast Cancer (DESTINY-Breast09)
该国际多中心部分非盲随机对照三期临床研究于2021年4月26日至2023年10月26日从亚欧美26个国家279个研究中心入组HER2阳性乳腺癌进展或转移尚未化疗或HER2靶向治疗患者1157例（其中半数来自亚洲）按1比1比1随机分为3组：德曲妥珠单抗＋帕妥珠单抗组383例、德曲妥珠单抗＋安慰剂组387例、紫杉类＋曲妥珠单抗＋帕妥珠单抗组387例。主要终点为无进展生存，由独立集中评审委员会盲法评定。次要终点包括客观缓解率、缓解持续期和安全性。
本次预设中期分析报告德曲帕组和紫曲帕组数据，德曲安组数据尚未揭盲。截至2025年2月26日，中位随访29.2个月，德曲帕组与紫曲帕组相比：
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中位无进展生存：40.7个月比26.9个月
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进展或死亡风险：减少44%（风险比：0.56，95%置信区间：0.44至0.71，P<0.00001，低于预设优效界值0.00043）
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确认客观缓解率：85.1%比78.6%
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确认完全缓解率：15.1%比8.5%
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中位缓解持续期：39.2个月比26.4个月
安全性与各治疗方案已知安全性特征一致，德曲帕组最常见不良事件为中性粒细胞减少、低血钾和贫血，紫曲帕组最常见不良事件为中性粒细胞减少、白细胞减少和腹泻。德曲帕组与紫曲帕组相比，不良事件发生率：
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≥3级不良事件：63.5%比62.3%
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确定药物相关肺间质病或肺实质炎：12.1%（44例1或2级，2例死于5级）比1.0%（均为1或2级）
因此，该研究结果表明，对于HER2阳性晚期乳腺癌一线治疗，德曲妥珠单抗＋帕妥珠单抗两药联合与紫杉类＋曲妥珠单抗＋帕妥珠单抗三药联合相比，进展或死亡风险显著减少44%，且未发现新的安全问题。
N Engl J Med. 2025 Oct 29. IF: 78.5
Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer.
Tolaney SM, Jiang Z, Zhang Q, Barroso-Sousa R, Park YH, Rimawi MF, Saura C, Schneeweiss A, Toi M, Chae YS, Kemal Y, Chaudhari M, Sendur MAN, Yamashita T, Casalnuovo M, Danso MA, Liu J, Shetty J, Herbolsheimer P, Loibl S; DESTINY-Breast09 Trial Investigators.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA; Fifth Medical Center of People's Liberation Army General Hospital, Beijing, China; Harbin Medical University Cancer Hospital, Harbin, China; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, USA; Brock Cancer Center, Virginia Oncology Associates, Norfolk, VA, USA; Brock Cancer Center, Sarah Cannon Research Institute, Norfolk, VA, USA; AstraZeneca, San Francisco, CA, USA; AstraZeneca, Gaithersburg, MD, USA; Brasilia Hospital, Rede Américas, Brasilia, Brazil; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Kyungpook National University Chilgok Hospital, Kyungpook National University School of Medicine, Daegu, Korea; Vall d'Hebron University Hospital, Barcelona, Spain; National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany; Johann Wolfgang Goethe Universitat, Frankfurt am Main, Germany; German Breast Group, Frankfurt am Main, Germany; Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan; Kanagawa Cancer Center, Yokohama, Japan; Faculty of Medicine, Altinbas University, Istanbul, Turkey; Ankara Yildirim Beyazit University, Ankara Bilkent City Hospital, Ankara, Turkey; HCG Manavata Cancer Center, Mumbai Naka, Nashik, India; LUCEN, Buenos Aires, Argentina.
BACKGROUND: Trastuzumab deruxtecan has shown efficacy in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer. The efficacy and safety of trastuzumab deruxtecan in patients with no previous therapy for HER2-positive advanced or metastatic breast cancer are unclear.
METHODS: We conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease. Patients were randomly assigned in a 1:1:1 ratio to receive trastuzumab deruxtecan plus pertuzumab; trastuzumab deruxtecan plus placebo; or a taxane, trastuzumab, and pertuzumab (THP). The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included objective response, duration of response, and safety.
RESULTS: For this prespecified interim analysis, data for trastuzumab deruxtecan plus pertuzumab and for THP are reported; data for trastuzumab deruxtecan plus placebo remain blinded until the final analysis of progression-free survival. At the data-cutoff date (February 26, 2025), the median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab (383 patients) and 26.9 months with THP (387 patients) (hazard ratio for progression or death, 0.56; 95% confidence interval [CI], 0.44 to 0.71; P<0.00001 [P-value boundary for superiority, 0.00043]). The incidence of a confirmed response was 85.1% with trastuzumab deruxtecan plus pertuzumab and 78.6% with THP (complete responses in 15.1% and 8.5%, respectively), with a median duration of response of 39.2 months and 26.4 months. Safety was consistent with the known profiles of the individual treatments. The incidence of grade 3 or higher adverse events was 63.5% with trastuzumab deruxtecan plus pertuzumab and 62.3% with THP; the most common were neutropenia, hypokalemia, and anemia with trastuzumab deruxtecan plus pertuzumab and neutropenia, leukopenia, and diarrhea with THP. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving trastuzumab deruxtecan plus pertuzumab (grade 1 or 2 in 44 patients and grade 5 [death] in 2 patients) and in 1.0% of those receiving THP (all grade 1 or 2).
CONCLUSIONS: Trastuzumab deruxtecan plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals.
Funded by AstraZeneca and Daiichi Sankyo
DESTINY-Breast09 ClinicalTrials.gov number: NCT04784715
PMID: 41160818
DOI: 10.1056/NEJMoa2508668
