难治型晚期乳腺癌曲妥珠德卢替康疗效
曲妥珠单抗德卢替康（DS-8201）是一种大分子HER2单克隆抗体与小分子细胞毒性拓扑异构酶I抑制剂的缀合物，由可被肿瘤组织酶分解的四肽基连接而成。根据一期临床剂量研究结果，曲妥珠单抗德卢替康对大多数晚期HER2阳性乳腺癌患者有效（缓解持续时间中位20.7个月）。曲妥珠单抗德卢替康对于既往曲妥珠单抗恩特星（T-DM1）治疗失败的HER2阳性乳腺癌转移患者，疗效尚待证实。
2019年12月11日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》和全球乳腺癌学术会议之首、美国圣安东尼奥乳腺癌论坛同时发表美国纽约纪念医院斯隆凯特林癌症中心、弗吉尼亚肿瘤医院、洛杉矶加利福尼亚大学、第一三共、哈佛大学达纳法伯癌症研究院、西班牙巴塞罗纳大学、巴塞罗那和马德里奎隆医院、日本神奈川癌症中心、东京国立癌症中心医院、日本癌症研究会有明医院、昭和大学、爱知癌症中心、近畿大学、四国癌症中心、九州癌症中心、韩国成均馆大学三星首尔医院、蔚山大学首尔峨山医院、延世大学、首尔大学、京畿道国家癌症中心、法国巴黎第十一大学（南巴黎大学）古斯塔夫鲁西研究院、欧仁马奎斯癌症中心的DESTINY-Breast01研究报告，探讨了曲妥珠单抗德卢替康治疗HER2阳性晚期乳腺癌T-DM1治疗失败患者的效果。
DESTINY-Breast01: DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer: A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1 (NCT03248492)
2019 SABCS GS1-03: [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01)
该国际多中心非盲单组两部分二期临床研究与2017年10月～2018年9月从北美洲、亚洲和欧洲72家医院入组既往T-DM1治疗失败的病理确诊HER2阳性乳腺癌转移患者253例。研究第一部分，给予患者三种不同剂量的曲妥珠单抗德卢替康：184例每公斤体重5.4毫克、48例每公斤体重6.4毫克、21例每公斤体重7.4毫克，以确定推荐剂量；研究第二部分，对推荐剂量的有效性和安全性进行分析。主要研究终点为经过独立集中复核的客观缓解率。次要关键终点为疾病控制率、临床获益率、缓解持续时间、无进展生存、安全性。
结果，确定推荐剂量为每公斤体重5.4毫克，这184例患者既往接受过中位6种治疗方案。根据意向治疗分析：
客观缓解比例：60.9%（95%置信区间：53.4～68.0）
中位随访时间：11.1个月（范围：0.7～19.9）
中位缓解持续时间：14.8个月（95%置信区间：13.8～16.9）
中位无进展生存：16.4个月（95%置信区间：12.7～尚未达到）
研究期间，发生率最高的≥3级不良事件：
中性粒细胞计数减少：20.7%
贫血：8.7%
恶心：7.6%
根据独立判断，研究药物与间质性肺疾病相关的患者占13.6%：
1～2级：10.9%
3～4级：0.5%
5级：2.2%
因此，该研究结果表明，对于既往T-DM1治疗失败的HER2阳性乳腺癌转移患者，曲妥珠单抗德卢替康的抗肿瘤活性持续超过12个月。除了恶心和骨髓抑制，亚组患者可见间质性肺疾病，故需注意肺部症状并密切监测。
该研究通讯作者：Ian Krop
N Engl J Med. 2019 Dec 11. [Epub ahead of print]
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.
Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A. Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Ian Krop; DESTINY-Breast01 Investigators.
Memorial Sloan Kettering Cancer Center, New York; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Institute of Oncology, Quiron Group, Barcelona and Madrid; Kanagawa Cancer Center, Yokohama; National Cancer Center Hospital, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Advanced Cancer Translational Research Institute, Showa University, Tokyo; Aichi Cancer Center Hospital, Nagoya; Kindai University Faculty of Medicine, Osaka; Shikoku Cancer Center, Matsuyama; National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; Samsung Medical Center, Asan Medical Center, University of Ulsan College of Medicine; Yonsei Cancer Center, Yonsei University Health System; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul; National Cancer Center, Gyeonggi, Korea; Institut Gustave Roussy, Université Paris-Sud, Villejuif; Centre Eugène Marquis, Rennes, France; US Oncology Network, Virginia Cancer Specialists, Arlington; University of California, Los Angeles-Jonsson Comprehensive Cancer Center, Los Angeles; Daiichi Sankyo, Basking Ridge, NJ; Dana-Farber Cancer Institute, Boston.
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.
Funded by Daiichi Sankyo and AstraZeneca
DESTINY-Breast01 ClinicalTrials.gov number: NCT03248492
DOI: 10.1056/NEJMoa1914510