Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan.
Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
Lancet Oncol. 2017 Nov;18(11):1512-1522. doi: 10.1016/S1470-2045(17)30604-6. Epub 2017 Oct 13.
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.
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.
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.
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.
Daiichi Sankyo Co, Ltd.
抗体药物偶联物已成为癌症治疗的一种强有力策略，它结合了单克隆抗体特异性靶向肿瘤细胞的能力和具有有效载荷的药物的高效杀伤活性，而这些有效载荷对于全身给药来说毒性太大。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、一种新型酶可切割接头和一种拓扑异构酶 I 抑制剂有效载荷组成。我们评估了它在晚期乳腺癌和胃或胃食管肿瘤患者中的安全性和耐受性。
这是一项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。符合条件的患者年龄至少为 20 岁，患有对标准治疗无反应的晚期乳腺癌或胃或胃食管癌，无论 HER2 状态如何。参与者接受曲妥珠单抗 deruxtecan 的初始静脉剂量为 0.8 至 8.0mg/kg，并在 21 天的周期内评估剂量限制毒性；此后，根据需要实施剂量减少，并且患者每 3 周接受一次治疗，直到出现不可接受的毒性作用或疾病进展。主要终点包括确定安全性和最大耐受剂量或推荐的 2 期剂量，并在至少接受一次研究药物剂量的所有参与者中进行分析。剂量递增研究是两部分研究的第一部分，第二部分剂量扩展部分于 2017 年 7 月 8 日在日本和美国开始招募患者。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02564900。
在 2015 年 8 月 28 日至 2016 年 8 月 26 日期间，共有 24 名患者入组并接受了曲妥珠单抗 deruxtecan 治疗（n=3 用于 0.8、1.6、3.2 和 8.0mg/kg 剂量；n=6 用于 5.4 和 6.4mg/kg 剂量）。截至 2017 年 2 月 1 日的研究截止日期，没有发生剂量限制毒性作用、实质性心血管毒性作用或死亡。一名患者因目标病灶分析不足而被从疗效分析中剔除。最常见的 3 级不良事件是淋巴细胞减少（n=3）和中性粒细胞计数减少（n=2）；一名患者报告出现 4 级贫血。一名患者报告了 3 例严重不良事件-发热性中性粒细胞减少症、肠穿孔和胆管炎。在 23 名可评估患者中，包括 6 名低 HER2 表达肿瘤患者，共有 10 名患者达到客观缓解（43%，95%CI 23.2-65.5）。23 名患者中有 21 名（91%；95%CI 72.0-98.9）达到疾病控制。中位随访时间为 6.7 个月（IQR 4.4-10.2），在 5.4mg/kg 或更高剂量下观察到 10 次反应中的 9 次（90%）。
曲妥珠单抗 deruxtecan 的最大耐受剂量尚未达到。在这项小型、预处理严重的研究人群中，曲妥珠单抗 deruxtecan 显示出抗肿瘤活性，甚至在低 HER2 表达的肿瘤中也是如此。基于安全性和疗效，最有可能的推荐 2 期剂量为 5.4 或 6.4mg/kg。
第一三共株式会社。
