曲妥珠单抗-德卢替康（DS-8201A）是人源化抗HER2靶向抗体曲妥珠单抗与DNA双螺旋拓扑异构酶I抑制剂化疗药德卢替康由可裂解肽连接而成。2017年，英国《柳叶刀》肿瘤学分册已经报告了DS-8201A用于HER2阳性晚期乳腺癌曲妥珠单抗-恩特星（T-DM1）治疗失败患者的一期两部分多中心非随机非盲多剂量临床研究第一部分（剂量递增阶段），确定了第二部分（剂量扩大阶段）每公斤体重5.4或6.4毫克的推荐剂量。
NCT02564900: Phase 1, Two-Part, Multicenter, Non-randomized, Open-label, Multiple Dose First-In-Human Study of DS-8201A, in Subjects With Advanced Solid Malignant Tumors
2019年4月29日，英国《柳叶刀》肿瘤学分册在线发表日本国立癌症中心医院、昭和大学、近畿大学、癌研有明医院、爱知癌症中心医院、博爱会相良医院、国立癌症中心东院、美国哈佛大学医学院达纳法伯癌症研究所、圣地亚哥夏普医疗中心、圣路易斯华盛顿大学、德克萨斯大学MD安德森癌症中心、路易斯维尔大学、纽约纪念医院斯隆凯特林癌症中心、第一三共株式会社的第二部分（剂量扩大阶段）研究报告，公布了DS-8201A推荐剂量用于HER2阳性晚期乳腺癌T-DM1治疗失败患者的安全和短期疗效结果。
该研究于2015年8月28日～2018年8月10日从8家美国医院和6家日本医院入组年龄≥18岁美国女性或≥20岁日本女性晚期乳腺癌T-DM1治疗失败患者118例（无论剂量递增阶段HER2表达如何或剂量扩大阶段HER2表达或突变如何），剂量扩大阶段每3周静脉注射推荐剂量DS-8201A每公斤体重5.4或6.4毫克，直至患者要求退出研究或毒性反应无法耐受或疾病恶化。主要研究终点为安全和短期疗效（由研究者评定的客观缓解患者比例）。对接受至少一次剂量扩大阶段推荐剂量DS-8201A并且疗效数据完整的所有患者进行疗效分析。对接受至少一次剂量扩大阶段推荐剂量DS-8201A的所有患者进行安全分析。
结果，115例患者接受至少一次剂量扩大阶段推荐剂量DS-8201A，所有患者发生至少一次治疗相关不良反应，≥3级治疗相关不良反应包括：
血红蛋白减少：17例（17%）
中性粒细胞减少：16例（14%）
白细胞减少：10例（9%）
血小板减少：9例（8%）
严重不良反应：22例（19%）
此外，研究者报告肺间质病变、肺实质炎症或肺组织炎症20例，包括3级不良反应1例和肺实质炎症所致治疗相关死亡2例。治疗无关死亡1例，由于疾病恶化。
其中，111例患者疗效数据完整，确认客观缓解66例（59.5%，95%置信区间：49.7～68.7）。
因此，该研究结果表明，对于T-DM1治疗失败的HER2阳性乳腺癌患者，DS-8201A的不良反应可控、短期疗效可观，故有必要进一步对HER2阳性乳腺癌开展二期和三期临床研究。
对此，意大利都灵大学医学院癌症研究所发表同期评论：HER2阳性肿瘤治疗新选手。
相关阅读
Lancet Oncol. 2019 Apr 29. [Epub ahead of print]
Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study.
Kenji Tamura, Junji Tsurutani, Shunji Takahashi, Hiroji Iwata, Ian E Krop, Charles Redfern, Yasuaki Sagara, Toshihiko Doi, Haeseong Park, Rashmi K Murthy, Rebecca A Redman, Takahiro Jikoh, Caleb Lee, Masahiro Sugihara, Javad Shahidi, Antoine Yver, Shanu Modi.
National Cancer Center Hospital, Tokyo, Japan; Showa University, Tokyo, Japan; Kindai University Faculty of Medicine, Osaka, Japan; The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Aichi Cancer Center Hospital, Nagoya, Japan; Dana-Farber Cancer Institute, Boston, MA, USA; Sharp HealthCare, San Diego, CA, USA; Social Medical Corporation Hakuaikai Sagara Hospital, Kagoshima, Japan; National Cancer Center Hospital East, Kashiwa, Japan; Washington University School of Medicine, St Louis, MO, USA; University of Texas MD Anderson Cancer Center, Houston, TX, USA; University of Louisville, Louisville, KY, USA; Daiichi Sankyo, Inc, Basking Ridge, NJ, USA; Daiichi Sankyo Co, Ltd, Tokyo, Japan; Memorial Sloan Kettering Cancer Center, New York, NY, USA.
BACKGROUND: Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5.4 mg/kg or 6.4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion.
METHODS: We did an open-label, dose-escalation and dose-expansion phase 1 trial at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years of age in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5.4 mg/kg or 6.4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with HER2-positive breast cancer has been completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978.
FINDINGS: Between Aug 28, 2015, and Aug 10, 2018, 115 of 118 patients with HER2-positive breast cancer were treated with at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. Frequent grade 3 or worse treatment-emergent adverse events included anaemia (19 [17%] of 115) and decreased neutrophil (16 [14%]), white blood cell (ten [9%]), and platelet (nine [8%]) counts. At least one serious treatment-emergent adverse event occurred for 22 (19%) patients. Investigators reported 20 cases of interstitial lung disease, pneumonitis, or organising pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. One death unrelated to study treatment was due to progressive disease. 66 (59.5%; 95% CI 49.7-68.7) of 111 patients had a confirmed objective response.
INTERPRETATION: Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in trastuzumab emtansine-pretreated patients with HER2-positive breast cancer. These results suggest that further development in phase 2 and 3 clinical trials for HER2-positive breast cancer is warranted.
FUNDING: Daiichi Sankyo Co, Ltd.
DOI: 10.1016/S1470-2045(19)30097-X
Lancet Oncol. 2019 Apr 29. [Epub ahead of print]
A new player in the treatment of HER2-positive tumours.
Gaia Giannone, Filippo Montemurro.
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
DOI: 10.1016/S1470-2045(19)30168-8
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