近日，美国纪念斯隆-凯特琳癌症中心Shanu Modi联合达纳法伯癌症研究所Ian Krop研究组的最新研究提出，曲妥珠单抗Deruxtecan可有效HER2阳性乳腺癌。这一研究成果于2019年12月11日发表在国际顶尖学术期刊《新英格兰医学杂志》上。

曲妥珠单抗Deruxtecan（DS-8201）是由抗HER2（人表皮生长因子受体2）抗体、可切割的四肽连接体和细胞毒性拓扑异构酶I抑制剂组成的抗体-药物偶联物。在第1阶段的剂量发现研究中，大多数HER2阳性的晚期乳腺癌患者对曲妥珠单抗Deruxtecan有效。

在这项两部分、开放标签、单组、多中心、临床2期的研究中，研究组招募了184名HER2阳性转移性乳腺癌成人患者，之前接受过曲妥珠单抗-美坦新治疗。研究的第一部分评估三种不同剂量的曲妥珠单抗Deruxtecan以确定推荐剂量；第二部分评估推荐剂量的疗效和安全性。

总体来说，184名先前平均接受过6次治疗的患者接受了推荐剂量的曲妥珠单抗Deruxtecan，即每公斤体重5.4mg。在意向治疗分析中，112名（60.9%）患者缓解。中位随访11.1个月后，中位缓解持续时间为14.8个月，无进展生存时间为16.4个月。在研究期间，最常见的3级及以上不良事件主要为中性粒细胞减少（20.7%）、贫血（8.7%）和恶心（7.6%）。经独立判断，13.6%的患者与试验药物有关。

总之，曲妥珠单抗Deruxtecan治疗HER2阳性转移性乳腺癌显示了持久的抗肿瘤活性。除恶心和骨髓抑制外，还在亚组患者中发现间质性肺疾病，需认真监测。

附：英文原文

Title: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer | NEJM

Author: Shanu Modi, M.D.,, Cristina Saura, M.D., Ph.D.,, Toshinari Yamashita, M.D.,, Yeon Hee Park, M.D.,, Sung-Bae Kim, M.D., Ph.D.,, Kenji Tamura, M.D., Ph.D.,, Fabrice Andre, M.D., Ph.D.,, Hiroji Iwata, M.D., Ph.D.,, Yoshinori Ito, M.D.,, Junji Tsurutani, M.D., Ph.D.,, Joohyuk Sohn, M.D., Ph.D.,, Neelima Denduluri, M.D.,, Christophe Perrin, M.D.,, Kenjiro Aogi, M.D., Ph.D.,, Eriko Tokunaga, M.D.,, Seock-Ah Im, M.D., Ph.D.,, Keun Seok Lee, M.D., Ph.D.,, Sara A. Hurvitz, M.D.,, Javier Cortes, M.D., Ph.D.,, Caleb Lee, M.D., Ph.D.,, Shuquan Chen, Ph.D.,, Lin Zhang, M.D., Ph.D.,, Javad Shahidi, M.D.,, Antoine Yver, M.D.,, and Ian Krop, M.D., Ph.D.

Issue&Volume: December 11, 2019

Abstract: 

BACKGROUND
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.

METHODS
In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.

RESULTS
Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).

CONCLUSIONS
Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. 

DOI: 10.1056/NEJMoa1914510

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1914510