近日，美国哈佛医学院Sara M. Tolaney团队研究了曲妥珠单抗deruxtecan联合帕妥珠单抗治疗HER2阳性转移性乳腺癌的效果与安全性。该项研究成果发表在2025年10月29日出版的《新英格兰医学杂志》上。

曲妥珠单抗deruxtecan对先前治疗过的人表皮生长因子受体2 （HER2）阳性晚期或转移性乳腺癌患者显示出疗效。目前尚不清楚曲妥珠单抗deruxtecan治疗初治的HER2阳性晚期或转移性乳腺癌患者的疗效和安全性。

研究组开展了一项3期试验，纳入了HER2阳性晚期或转移性乳腺癌患者，这些患者之前没有接受过化疗或HER2定向治疗的转移性疾病。患者以1:1:1的比例随机分配接受曲妥珠单抗deruxtecan+帕妥珠单抗；曲妥珠单抗加安慰剂；或紫杉烷、曲妥珠单抗和帕妥珠单抗（THP）。主要终点是通过盲法独立中心评价的无进展生存期。次要终点包括客观缓解、缓解持续时间和安全性。

对于这个预先指定的中期分析，研究组报道了曲妥珠单抗deruxtecan+帕妥珠单抗和THP的数据；曲妥珠单抗加安慰剂的数据在无进展生存期的最终分析之前仍然是盲的。截至数据截止日期（2025年2月26日），曲妥珠单抗deruxtecan联合帕妥珠单抗组（383例）的中位无进展生存期为40.7个月，THP组（387例）的中位无进展生存期为26.9个月（进展或死亡的风险比为0.56；95%可信区间为0.44 - 0.71;P<0.00001[优势p值边界为0.00043]）。

曲妥珠单抗-deruxtecan联合帕妥珠单抗的确诊缓解发生率为85.1%，THP的确诊缓解发生率为78.6%（完全缓解分别为15.1%和8.5%），中位缓解持续时间为39.2个月和26.4个月。安全性与已知的单个治疗方案一致。曲妥珠单抗+deruxtecan组3级或以上不良事件的发生率为63.5%，THP组为62.3%；最常见的是中性粒细胞减少症、低钾血症和贫血合并曲妥珠单抗加普妥珠单抗、中性粒细胞减少症、白细胞减少症和腹泻合并THP。在接受曲妥珠单抗-deruxtecan联合帕妥珠单抗治疗的患者中，12.1%的患者发生药物相关性间质性肺病或肺炎（44例患者为1级或2级，2例患者为5级[死亡]），而接受THP治疗的患者中，这一比例为1.0%（均为1级或2级）。

研究结果表明，当用作HER2阳性晚期或转移性乳腺癌的一线治疗时，曲妥珠单抗与deruxtecan联合帕妥珠单抗导致进展或死亡风险显著低于THP，没有新的安全性信号。

附：英文原文

Title: Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer

Author: Sara M. Tolaney, Zefei Jiang, Qingyuan Zhang, Romualdo Barroso-Sousa, Yeon Hee Park, Mothaffar F. Rimawi, Cristina Saura, Andreas Schneeweiss, Masakazu Toi, Yee Soo Chae, Yasemin Kemal, Mukesh Chaudhari, Mehmet A.N. endur, Toshinari Yamashita, Monica Casalnuovo, Michael A. Danso, Jie Liu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl

Issue&Volume: 2025-10-29

Abstract:

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.

DOI: NJ202510290000007

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2508668