Background

Antibody–drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody–drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours.

Methods

This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900.

Findings

Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events—febrile neutropenia, intestinal perforation, and cholangitis—were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2–65·5). Disease control was achieved in 21 (91%; 95% CI 72·0–98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4–10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater.

Interpretation

The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg.

Funding

Daiichi Sankyo Co, Ltd.

中文翻译：

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曲妥珠单抗deruxtecan（DS-8201）（一种靶向HER2的抗体-药物结合物）在患有晚期乳腺和胃或胃食管肿瘤的患者中的安全性，药代动力学和抗肿瘤活性：1期剂量递增研究

背景

抗体-药物偶联物已成为癌症治疗中的一种强大策略，将单克隆抗体特异性靶向肿瘤细胞的能力与对系统给药毒性太大的有效载荷药物的高效杀伤活性结合在一起。曲妥珠单抗deruxtecan（也称为DS-8201）是一种抗体-药物偶联物，由针对HER2的人源化抗体，新型酶可裂解的连接子和拓扑异构酶I抑制剂有效负载组成。我们评估了其对晚期乳腺癌和胃癌或胃食管肿瘤患者的安全性和耐受性。

方法

这是在日本的两个研究地点进行的开放标签，剂量递增的1期试验。符合条件的患者至少20岁，无论其HER2状况如何，均对标准治疗无效，但患有乳腺癌，胃癌或胃食管癌。参与者接受曲妥珠单抗deruxtecan的初始静脉内剂量为0·8至8·0 mg / kg，并在21天的周期内评估了剂量限制毒性；此后，根据需要降低剂量，并每3周治疗一次患者，直到产生不可接受的毒性作用或疾病进展为止。主要终点包括安全性鉴定和最大耐受剂量或推荐的2期剂量，并在接受至少一种剂量研究药物的所有参与者中进行了分析。剂量增加研究是两部分研究的第一部分，第二部分是剂量扩大研究，截至2017年7月8日在日本和美国进行并招募患者。该试用版的注册地址为ClinicalTrials.gov，编号NCT02564900。

发现

在2015年8月28日至2016年8月26日期间，招募了24名患者并接受曲妥珠单抗德鲁替康（0·8、1·6、3·2和8·0 mg / kg剂量分别为n = 3； n = 5·4和6·4 mg / kg分别为6。截至研究截止日期2017年2月1日，未发生剂量限制性毒性作用，实质性心血管毒性作用或死亡。从活动分析中删除了一名患者，因为他们没有足够的目标病灶进行分析。最常见的3级不良反应是淋巴细胞减少（n = 3）和嗜中性粒细胞减少（n = 2）；1例患者报告有4级贫血。每个患者报告了三个严重的不良事件，即发热性中性粒细胞减少，肠穿孔和胆管炎。总体而言，在23例可评估患者中，包括6例HER2表达低的患者，10名患者达到了客观缓解（43％，95％CI 23·2–65·5）。23名患者中有21名（91％； 95％CI 72·0–98·9）实现了疾病控制。中位随访时间为6·7个月（IQR 4·4-10·2），在5·4 mg / kg或更高剂量下，十个反应中有九个（90％）出现。

解释

未达到曲妥珠单抗deruxtecan的最大耐受剂量。在这个经过大量预处理的小型研究人群中，曲妥珠单抗deruxtecan甚至在低HER2表达肿瘤中也显示出抗肿瘤活性。基于安全性和活动性，最可能推荐的第2阶段推荐剂量为5·4或6·4 mg / kg。

资金

第一三共株式会社