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曲妥珠单抗多卡马嗪（SYD985）是荷兰奈梅亨合成子生物制药研发的HER2靶向抗体与化疗药结合物，由曲妥珠单抗与含有多卡霉素（倍癌霉素）的化疗药共价结合而成，临床前研究表明对于各种动物模型的抗肿瘤活性令人鼓舞。 2019年6月27日，英国《柳叶刀》肿瘤学分册在线发表英国伦敦大学癌症研究院、皇家马斯登医院、曼彻斯特大学克里斯蒂医院、牛津大学丘吉尔医院、格拉斯哥西苏格兰比特森癌症中心、马里兰大学格林鲍姆综合癌症中心、荷兰奈梅亨大学医疗中心、格罗宁根大学医疗中心、阿姆斯特丹列文虎克医院荷兰癌症研究所、鹿特丹大学医疗中心、奈梅亨合成子生物制药、西班牙巴塞罗那大学瓦尔德希布伦医院肿瘤研究所、马德里自治大学希门尼斯迪亚兹医院、克拉拉坎帕尔综合癌症中心、巴塞罗那大学生物医学研究所、加泰罗尼亚肿瘤研究所、比利时安特卫普大学医院、根特大学医院、布鲁塞尔自由大学朱尔博尔代研究所的首次人体研究SYD985.001报告，探讨了曲妥珠单抗多卡马嗪治疗局部晚期和转移性实体肿瘤和HER2表达乳腺癌的安全性、药物代谢动力学和活性。 SYD985.001: First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients: A Two Part First-in-human Phase I Study (With Expanded Cohorts) With the Antibody-drug Conjugate SYD985 to Evaluate the Safety, Pharmacokinetics and Efficacy in Patients With Locally Advanced or Metastatic Solid Tumors (NCT02277717) 该一期剂量递增和剂量扩大两阶段临床研究于2014年10月30日～2018年4月2日进行入组治疗：
每3周第1天静脉注射曲妥珠单抗多卡马嗪，剂量递增阶段曲妥珠单抗多卡马嗪从每公斤体重0.3毫克递增至2.4毫克（按3＋3设计）直至疾病进展或毒性反应无法耐受。主要终点：
结果：
因此，该研究结果表明，对于难治型HER2表达转移性癌症（包括HER2阳性曲妥珠单抗恩特星T-DM1耐药和HER2低表达乳腺癌）患者，曲妥珠单抗多卡马嗪的临床有效性显著、安全性可控。目前，曲妥珠单抗多卡马嗪治疗HER2阳性乳腺癌的进一步研究正在进行，HER2低表达乳腺癌和其他HER2表达癌症的研究正在准备。 对此，法国斯特拉斯堡医院保罗施特劳斯中心发表同期评论：抗体与化疗药结合物家族新成员。 Lancet Oncol. 2019 Jun 27. [Epub ahead of print] Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Udai Banerji, Carla M L van Herpen, Cristina Saura, Fiona Thistlethwaite, Simon Lord, Victor Moreno, Iain R Macpherson, Valentina Boni, Christian Rolfo, Elisabeth G E de Vries, Sylvie Rottey, Jill Geenen, Ferry Eskens, Marta Gil-Martin, Ellen C Mommers, Norbert P Koper, Philippe Aftimos. Institute of Cancer Research and The Royal Marsden, London, UK; Radboud University Medical Center, Nijmegen, Netherlands; Vall d'Hebrón University Hospital, Vall d'Hebrón Institute of Oncology, Barcelona, Spain; The Christie NHS Foundation Trust and The University of Manchester, Manchester, UK; The Churchill Hospital, Oxford, UK; START Madrid-FJD, Madrid, Spain; Beatson West of Scotland Cancer Center, Glasgow, UK; START-Madrid-CIOCC, Madrid, Spain; University Hospital Antwerp, Edegem, Belgium; Greenebaum Comprehensive Cancer Center, Maryland University, Baltimore, MD, USA; University Medical Center Groningen, Groningen, Netherlands; Ghent University Hospital, Ghent, Belgium; The Netherlands Cancer Institute, Amsterdam, Netherlands; Erasmus Medical Center, Rotterdam, Netherlands; Institut Català d'Oncologia-IDIBELL, Barcelona, Spain; Synthon Biopharmaceuticals, Nijmegen, Netherlands; Institut Jules Bordet-Université Libre de Bruxelles, Brussels, Belgium. BACKGROUND: Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. METHODS: We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0.3 mg/kg to 2.4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FINDINGS: Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2.4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1.5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1.2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20.4-48.4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13.8-46.8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16.3-67.6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0.2-30.2) of 16 patients with gastric cancer, four (25%, 7.3-52.4) of 16 patients with urothelial cancer, and five (39%, 13.9-68.4) of 13 patients with endometrial cancer. INTERPRETATION: Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FUNDING: Synthon Biopharmaceuticals DOI: 10.1016/S1470-2045(19)30328-6 Lancet Oncol. 2019 Jun 27. [Epub ahead of print] A new agent in the family of antibody-drug conjugates. Xavier Pivot, Thierry Petit. Centre Paul Strauss, Porte de l'Hopital Strasbourg, Strasbourg, France. DOI: 10.1016/S1470-2045(19)30402-4
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