對于HER2陽性早期乳腺癌高風(fēng)險患者，術(shù)前治療可顯著降低風(fēng)險，現(xiàn)有標準方案是曲妥珠單抗＋帕妥珠單抗＋化療。不過，現(xiàn)有方案毒性較高，且療效欠佳。德曲妥珠單抗由1個曲妥珠單抗大分子與7～8個化療藥物德魯替康小分子通過可分解四肽綴合而成，如同攜帶多枚核彈頭的制導(dǎo)火箭，可靶向癌細胞釋放高濃度化療藥物，已被DESTINY-Breast03和DESTINY-Breast09研究先后證實對HER2陽性晚期乳腺癌二線治療和一線治療顯著優(yōu)于現(xiàn)有標準方案，那么對HER2陽性早期乳腺癌高風(fēng)險患者術(shù)前治療是否有效？

　　2025年10月21日，歐洲腫瘤內(nèi)科學(xué)會官方期刊《腫瘤學(xué)年鑒》在線發(fā)表復(fù)旦大學(xué)附屬腫瘤醫(yī)院吳炅、天津市腫瘤醫(yī)院曹旭晨、河南省腫瘤醫(yī)院劉真真、桃園長庚紀念醫(yī)院陳訓(xùn)徹等來自18個國家和地區(qū)147家醫(yī)院學(xué)者的DESTINY-Breast11研究報告，首次對高風(fēng)險HER2陽性早期乳腺癌術(shù)前德曲妥珠單抗單藥或聯(lián)合曲妥珠單抗＋帕妥珠單抗＋紫杉醇或多柔比星＋環(huán)磷酰胺聯(lián)合曲妥珠單抗＋帕妥珠單抗＋紫杉醇的有效性和安全性進行隨機分組比較。

• DESTINY-Breast11 (NCT05113251): Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer

• Official Title: A Phase 3 Open-label Trial of Neoadjuvant Trastuzumab Deruxtecan (T-DXd) Monotherapy or T-DXd Followed by THP Compared to ddAC-THP in Participants With High-risk HER2-positive Early-stage Breast Cancer (DESTINY-Breast11)

　　該國際多中心非盲隨機對照三期臨床研究于2021年10月25日至2025年3月12日從18個國家和地區(qū)147個研究中心入組高風(fēng)險（術(shù)前檢查腫瘤≥5厘米但淋巴結(jié)陰性或腫瘤任意大小但淋巴結(jié)陽性）HER2陽性早期乳腺癌成年女性患者927例，按1比1比1隨機為三組：286例單用德曲妥珠單抗8個周期、321例德曲妥珠單抗4個周期繼以紫杉醇＋曲妥珠單抗＋帕妥珠單抗4個周期、320例劑量密集多柔比星＋環(huán)磷酰胺4個周期繼以紫杉醇＋曲妥珠單抗＋帕妥珠單抗4個周期。根據(jù)獨立數(shù)據(jù)監(jiān)測委員會建議，單用德曲妥珠單抗入組于2024年3月13日提前結(jié)束。主要終點為全部入組患者的病理完全緩解（術(shù)后檢查腫瘤消失或未浸潤，且淋巴結(jié)陰性）。次要終點包括全部入組患者的無事件生存和實際用藥患者的安全性。

　　結(jié)果，德、德紫曲帕、多環(huán)紫曲帕的病理完全緩解率分別為43.0%、67.3%、56.3%。

德紫曲帕與多環(huán)紫曲帕相比，病理完全緩解率高11.2%（95%置信區(qū)間：4.0～18.3，P=0.003）亞組分析：

• 激素受體陽性：61.4%比52.3%（高9.1%，95%置信區(qū)間：0.2～17.9）

• 激素受體陰性：83.1%比67.1%（高16.1%，95%置信區(qū)間：3.0～28.8）

　　德紫曲帕與多環(huán)紫曲帕相比，中位無事件生存（成熟度4.5%）風(fēng)險比為0.56（95%置信區(qū)間：0.26～1.17）。

　　德、德紫曲帕、多環(huán)紫曲帕相比，不良事件發(fā)生率：

• ≥3級不良事件：22.6%、37.5%、55.8%

• 嚴重不良事件：10.2%、10.6%、20.2%

• 各級左心室功能障礙：0.7%、1.3%、6.1%

• 各級藥物相關(guān)肺間質(zhì)病或肺炎：4.9%、4.4%、5.1%

• 治療相關(guān)死亡：0、0.3%、0.6%

　　因此，該研究結(jié)果表明，對于HER2陽性早期乳腺癌高風(fēng)險患者，術(shù)前德曲妥珠單抗→紫杉醇＋曲妥珠單抗＋帕妥珠單抗與現(xiàn)有標準方案相比，病理完全緩解有統(tǒng)計學(xué)顯著性和臨床意義，并且安全性較高。

Ann Oncol. 2025 Oct 21. IF: 65.4

Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase 3 trial.

Nadia Harbeck, Shanu Modi, Lajos Pusztai, Shinji Ohno, Jiong Wu, Sung-Bae Kim, Atsushi Yoshida, Alessandra Fabi, Xuchen Cao, Rona Joseph, Rubi Li, Bogdan Zurawski, Santiago Escrivá-de-Romaní, Renata Meneguetti, Archara Supavavej, Shin-Cheh Chen, Zhenzhen Liu, Catherine Kelly, Giuseppe Curigliano, William F. Symmans, Mohammad Gufran, Jun Ke, Adam Konpa, Pia Herbolsheimer, Jean-Francois Boileau; DESTINY-Breast11 Trial Investigators.

LMU University Hospital and CCC Munich, Munich, Germany; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA; University of Texas MD Anderson Cancer Center, Houston, TX, USA; AstraZeneca, Waltham, MA, USA; AstraZeneca, Gaithersburg, MD, USA; Sagara Hospital, Kagoshima, Japan; St. Luke's International Hospital, Chuo-ku, Tokyo, Japan; Fudan University Shanghai Cancer Center, Shanghai, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University, Ministry of Education, Tianjin, China; Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; Chang Gung Memorial Hospital, Taoyüan, Taiwan, China; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; European Institute of Oncology, IRCCS, Milano, Italy; University of Milano, Milano, Italy; Regional Cancer Centre, Thiruvananthapuram, India; St Luke's Medical Center, Quezon City, Philippines; Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland; AstraZeneca, Warsaw, Poland; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Instituto de Pesquisa Hapvida Notredame, Sao Paulo, Brazil; Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, Thailand; Mater Private Hospital, Dublin and Cancer Trials Ireland Breast Group, Dublin, Ireland; AstraZeneca, Luton, UK; Montreal Jewish General Hospital, Segal Cancer Centre, McGill University, Montreal, QC, Canada.

HIGHLIGHTS

• DESTINY-Breast11 is the first phase 3 study to report T-DXd outcomes for high-risk, HER2-positive early breast cancer

• Neoadjuvant T-DXd-THP led to a statistically significant and clinically meaningful improvement in pCR rate versus ddAC-THP

• Safety also favoured T-DXd-THP, with lower rates of severe and serious adverse events and haematological toxicities

• These data support T-DXd-THP as a more effective and less toxic neoadjuvant treatment than anthracycline-based therapy

BACKGROUND: Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab+pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel+trastuzumab+pertuzumab (THP) versus dose-dense doxorubicin+cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3), HER2-positive disease.

PATIENTS AND METHODS: This open-label, phase 3 trial (147 sites, 18 countries) randomised adults 1:1:1 to T-DXd (×8 cycles), T-DXd-THP (4+4 cycles), or ddAC-THP (4+4 cycles). T-DXd-alone arm enrolment closed early following Independent Data Monitoring Committee recommendation. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population). Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set). ClinicalTrials.gov: NCT05113251; recruitment closed.

RESULTS: Between 25/10/2021 and 12/03/2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43.0% (T-DXd, n=123), 67.3% (T-DXd-THP, n=216), and 56.3% (ddAC-THP, n=180). T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2% (95% CI, 4.0, 18.3; p=0.003), with benefit in hormone receptor-positive (61.4% [n/N=145/236] vs 52.3% [n/N=123/235]; ΔpCR 9.1% [95% CI, 0.2, 17.9]) and -negative (83.1% [n/N=69/83] vs 67.1% [n/N=57/85]; ΔpCR 16.1% [95% CI, 3.0, 28.8]) subgroups. Median EFS (T-DXd-THP vs ddAC-THP, maturity 4.5%) hazard ratio was 0.56 [95% CI, 0.26, 1.17]). Grade ≥3 AE (T-DXd, 22.6% [n=64]; T-DXd-THP, 37.5% [n=120]; ddAC-THP, 55.8% [n=174]), serious AE (T-DXd, 10.2% [n=29]; T-DXd-THP, 10.6% [n=34]; ddAC-THP, 20.2% [n=63]), and all-grade left-ventricular dysfunction (T-DXd, 0.7% [n=2]; T-DXd-THP, 1.3% [n=4]; ddAC-THP, 6.1% [n=19]) rates were lower for T-DXd and T-DXd-THP than ddAC-THP. All-grade adjudicated drug-related interstitial lung disease/pneumonitis rates were low and similar across arms (T-DXd, 4.9% [n=14]; T-DXd-THP, 4.4% [n=14]; ddAC-THP, 5.1% [n=16]). Three treatment-related deaths occurred (T-DXd-THP, 0.3% [n=1]; ddAC-THP, 0.6% [n=2]).

CONCLUSIONS: Neoadjuvant T-DXd-THP demonstrated statistically significant and clinically meaningful pCR benefit and improved safety versus ddAC-THP.

KEYWORDS: neoadjuvant, early breast cancer, HER2-positive, trastuzumab deruxtecan, pathological complete response

DOI: 10.1016/j.annonc.2025.10.019