2012年，第一代抗体缀合药物恩美曲妥珠单抗被EMILIA研究证实对HER2阳性晚期乳腺癌优于当时二线治疗首选方案拉帕替尼＋卡培他滨，并于次年被美国和欧洲批准用于HER2阳性晚期乳腺癌二线治疗，再于2019年根据KATHERINE研究被美国和欧洲批准用于HER2阳性早期乳腺癌术前治疗。不过，直到2020年恩美曲妥珠单抗才被中国内陆批准用于HER2阳性早期乳腺癌术前治疗，再于次年被中国内陆批准用于HER2阳性晚期乳腺癌二线治疗，比拉帕替尼被中国内陆批准还久，当时曾经有人感慨：2012年自己还没结婚，现在孩子已上小学。此前，中国自主研发新药吡咯替尼已于2018年根据二期研究被火速批准用于HER2阳性晚期乳腺癌二线治疗，并于2022年根据PHEDRA研究被批准用于HER2阳性早期乳腺癌术前治疗，再于2023年根据PHILA研究被批准用于HER2阳性晚期乳腺癌一线治疗。那么，HER2阳性晚期乳腺癌吡咯替尼治疗失败后，恩美曲妥珠单抗疗效如何？
2025年9月26日，英国《自然》旗下《信号转导与靶向治疗》在线发表江苏省人民医院（南京医科大学第一附属医院）、南京医科大学公共卫生学院、安徽医科大学第二附属医院、苏州大学附属第一医院、南京医科大学第四附属医院的NJMU-BC02研究报告，首次对HER2阳性晚期乳腺癌吡咯替尼±曲妥珠单抗联合帕妥珠单抗治疗失败后恩美曲妥珠单抗的有效性、安全性和生物标志物进行探索。
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NJMU-BC02 (NCT06125834): Trastuzumab Emtansine (T-DM1) in HER2-positive Breast Cancer Patients With Progressive Disease After TKIs or HP Therapy
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Official Title: Trastuzumab Emtansine (T-DM1) Treatment in HER2-positive Breast Cancer Patients With Progressive Disease After TKIs or HP Therapy: a Multicenter, Single-arm, Phase II Study
该多中心单组二期临床研究于2023年10月至2025年3月从南京医科大学第一附属医院、安徽医科大学第二附属医院、苏州大学附属第一医院、南京医科大学第四附属医院入组HER2阳性晚期乳腺癌吡咯替尼治疗失败患者36例，每21天给予恩美曲妥珠单抗治疗，直至疾病进展或者毒性反应无法耐受。主要终点为客观缓解率，次要终点包括疾病控制率、临床获益率、无进展生存和毒性反应。
结果，截至2025年3月1日，中位随访12.8个月：
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客观缓解率：47.2%（95%置信区间：30.4～64.5）
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疾病控制率：66.7%（95%置信区间：49.0～81.4）
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临床获益率：50.0%（95%置信区间：32.9～67.1）
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无进展生存：中位6.6个月（95%置信区间：5.2～NA）
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毒性反应：可控
单细胞RNA测序显示：癌细胞周期活性越低、巨噬细胞和CD8阳性T细胞活性越高，恩美曲妥珠单抗疗效越好，并且已被HER2阳性早期乳腺癌术前治疗队列验证。
因此，该小样本初步研究结果表明，对于HER2阳性晚期乳腺癌吡咯替尼±曲妥珠单抗联合帕妥珠单抗治疗失败患者，恩美曲妥珠单抗有效且毒性反应可控，潜在的生物标志物可能有助于预测恩美曲妥珠单抗疗效，为解决恩美曲妥珠单抗耐药的新靶点提供参考。
不过，2023年DESTINY-Breast03研究已经证实，HER2阳性晚期乳腺癌曲妥珠单抗＋紫杉类治疗失败后，德曲妥珠单抗显著优于恩美曲妥珠单抗，已经成为二线治疗首选方案。2025年1月1日，中国新版医保目录正式执行，德曲妥珠单抗每支100毫克降至3480元，恩美曲妥珠单抗经过此前多轮降价每支100毫克为3580元……
Signal Transduct Target Ther. 2025 Sep 29;10:318. IF: 52.7
Tumor microenvironment delineates differential responders to trastuzumab emtansine in HER2-positive metastatic breast cancer patients previously treated with pyrotinib: an exploratory biomarker analysis of a phase II study (NJMU-BC02).
Pan H, Wang J, Sun Y, Li F, Sun C, Liu M, Xu H, Tao J, Mao X, Wang C, Wang S, Li W, Ding Q, Zhou W.
The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; School of Public Health, Nanjing Medical University, Nanjing, China; The Second Affiliated Hospital of Anhui Medical University, Hefei, China; The First Affiliated Hospital of Soochow University, Suzhou, China; The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive breast cancer. However, the efficacy of T-DM1 for patients after failure of pyrotinib and/or trastuzumab plus pertuzumab has not been clear. Additionally, no biomarker has been reported to predict the effect of T-DM1. In this multicenter phase II trial (NCT06125834), 36 participants with HER2-positive metastatic breast cancer were enrolled to receive T-DM1 therapy on a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included the disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and toxicity. The primary endpoint was an ORR of 47.2% (17/36, 95% CI 30.4-64.5). The treatment exhibited a manageable toxicity profile. The DCR was 66.7% (24/36, 95% CI 49.0-81.4), and the CBR was 50.0% (18/36, 95% CI 32.9-67.1). The median PFS was 6.6 (95% CI 5.2-NA) months. Single-cell RNA sequencing revealed that the low cell cycle activity of cancer cells, activated macrophages and CD8+ T cells was associated with the good efficacy of T-DM1, which was validated in a neoadjuvant cohort. This study suggests that T-DM1 is effective with a measurable safety profile in patients with metastatic HER2-positive breast cancer after failure of pyrotinib and/or trastuzumab plus pertuzumab. Our preliminary findings suggest potential biomarkers that may help predict T-DM1 efficacy, generating hypotheses for novel therapeutic targets that may address T-DM1 resistance.
PMID: 41016944
DOI: 10.1038/s41392-025-02409-2