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抗体与化疗药缀合物已经成为癌症治疗的有力方法，可以将单克隆抗体特异靶向肿瘤细胞的能力，与化疗药的高效杀伤活性相结合，并且大大减少化疗全身给药的毒性。曲妥珠单抗德鲁替康（DS-8201）即为抗体与化疗药缀合物，由针对HER2的人源化抗体曲妥珠单抗、新型可酶解拓扑异构酶I抑制剂德鲁替康结合而成。
2017年10月13日，英国《柳叶刀肿瘤学分册》在线发表日本千叶和东京国立癌症研究中心医院、日本和美国第一三共的研究报告，对曲妥珠单抗德鲁替康用于晚期乳腺癌和胃癌或胃食管肿瘤患者的安全性和耐受性进行了评定。 该非盲剂量递增一期研究研究于2015年8月28日～2016年8月26日在日本国立癌症研究中心分别位于千叶和东京的两家医院入组年龄≥20岁的标准疗法难治型（既往对曲妥珠单抗、T-DM1、帕妥珠单抗或拉帕替尼无效）乳腺癌17例、胃癌或胃食管癌患者7例，无论HER2情况如何，每3周接受剂量由0.8递增至8.0mg/kg的曲妥珠单抗德鲁替康静脉注射，并于每21天评定剂量限制性毒性反应；此后，如有需要可以减少剂量，并且每3周治疗1次直至毒性反应无法耐受或疾病进展为止。主要终点包括安全性和最大耐受剂量或推荐2期给药，并且对接受研究药物≥1次的所有参与者进行分析。剂量递增研究是两部分研究的第一部分，第二次部分给药扩展研究正在进行，已于2017年7月8日开始在日本和美国入组患者。该研究已在美国政府临床研究网站注册，编号：NCT02564900。 结果，接受曲妥珠单抗德鲁替康0.8、1.6、3.2、8.0mg/kg各3例，5.4、6.4mg/kg各6例。中位随访时间为6.7个月（四分位距：4.4～10.2）。 截至2017年2月1日的研究截止日期，未发生剂量限制性毒性反应、重大心血管毒性反应或死亡。最常见的3级不良事件为淋巴细胞减少3例、中性粒细胞减少2例；1例患者报告4级贫血。1例患者报告了3种严重不良事件（发热性中性粒细胞减少、肠穿孔、胆管炎）。 1例患者由于目标病变无法分析而从药物有效性分析移除，其余可评估患者23例，其中：
曲妥珠单抗德鲁替康未达最大耐受剂量。 因此，对于该小样本难治型研究人群，曲妥单抗德鲁替康显示出抗肿瘤活性，即使对于HER2低表达肿瘤。根据安全性和有效性，二期研究最可能推荐剂量为5.4或6.4mg/kg。 对此，康奈尔大学威尔医学院和纽约长老会医院实体肿瘤科发表同期评论：抗体与化疗药缀合物能否改善HER2阳性癌症的疗效？ Lancet Oncol. 2017 Oct 13. [Epub ahead of print] Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Toshihiko Doi, Kohei Shitara, Yoichi Naito, Akihiko Shimomura, Yasuhiro Fujiwara, Kan Yonemori, Chikako Shimizu, Tatsunori Shimoi, Yasutoshi Kuboki, Nobuaki Matsubara, Atsuko Kitano, Takahiro Jikoh, Caleb Lee, Yoshihiko Fujisaki, Yusuke Ogitani, Antoine Yver, Kenji Tamura. National Cancer Center Hospital East, Chiba, Japan; National Cancer Center Hospital, Tokyo, Japan; Daiichi Sankyo Co, Ltd, Tokyo, Japan; Daiichi Sankyo Inc, Basking Ridge, NJ, USA. 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. DOI: 10.1016/S1470-2045(17)30604-6 Lancet Oncol. 2017 Oct 13. [Epub ahead of print] Antibody-drug conjugates: can the payload improve activity in HER2 expressing cancers? Manish A Shah. Solid Tumor Oncology Service, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA. Antibody-drug conjugates represent a relatively new class of drugs in oncology and carry a great hope of using the exquisite sensitivity of the ligand-antibody complex to deliver a cytotoxic payload directly and specifically to malignant cells—a cancer treatment smart bomb. The seeds of this concept take us back over 110 years, when Paul Ehrlich first promoted his side-chain theory, postulating that specific receptors are associated with cells or can be distributed in the blood stream in response to a stimulus, or antigen[1]. Key drug design criteria to consider in the development of a successful antibody-drug conjugate include the antibody used to target malignancy (eg, delivery system), the cytotoxic drug being delivered (eg, payload), and the linker that allows for a stable drug in plasma as well as intracellular disassociation and optimal delivery of the payload within the cell. In The Lancet Oncology, Toshihiko Doi and colleagues[2] present the results of a phase 1 dose-escalation study of a novel antibody-drug conjugate, DS-8201, which links a potent topoisomerase I inhibitor (exatecan derivative) to a humanised anti-HER2 antibody. What makes this drug novel and exciting is that the enzymatically cleavable peptide-linker used allows for greater cargo and better delivery[3]. Specifically, DS-8201 has a drug-to-antibody ratio of 7-8 (eg, 7-8 molecules of the cytotoxic drug per antibody), whereas most antibody-drug conjugates have a drug-to-antibody ratio of 2-4, allowing greater and potentially more focused delivery of the cytotoxic drug. A comparator drug, T-DM1, also uses HER2 as the target, but uses a non-reducible thioether linker and a microtubule inhibitor DM1 (derivative of maytansine) as the payload and has a drug-to-antibody ratio of 3.5[4]. T-DM1 is quite effective, already approved for breast cancer on the basis of positive results seen in patients with breast cancer who had received one previous HER2-directed therapy in the EMILIA study[5], and in patients who had received at least two previous HER2-targeted therapies in the TH3RESA study[6,7]. However, T-DM1 was not effective in the second-line setting in HER2-positive gastric cancer when compared with taxane chemotherapy[8]. This study was a dose-finding study of trastuzumab deruxtecan, and has put forward doses of 5.4 mg/kg and 6.4 mg/kg in an ongoing expansion phase[2]. Although we will need a larger sample size, the preliminary data suggests that the drug is safe with perhaps a different safety profile than other antibody-drug conjugates, with observed toxic effects being gastrointestinal and myelosuppression. The challenge in terms of drug development for this drug is to identify a patient population in which the drug can show its own unique benefit. The novel antibody-drug conjugate design might show activity in patients who do not have high expression of HER2. This finding is likely to be the real impact of this novel compound as it moves forward. To place this drug in context then, I believe the seminal question is: do we have preliminary evidence of activity in low HER2-expressing tumours? Most patients enrolled on this phase 1 study were patients with breast cancer who had high expression of HER2. Among the nine patients that were not in the immunohistochemistry (IHC) 3+ category, two of the three patients who had a partial response to DS-8201 were fluorescence in-situ hybridisation (FISH)-positive. The third patient was notable—a patient with FISH-negative gastric cancer with HER2 IHC 2+. However, the concern with gastric cancer is the greater heterogeneity of HER2 expression[9]. Given this knowledge, and the fact that patients with HER2 IHC 1+ or 0 had no response to trastuzumab deruxtecan, the suggestion that trastuzumab deruxtecan might be effective even in patients with low HER2 expression and in cases of gastric cancer remains an important question. The authors' other primary claim is that this drug is more tolerable than other antibody-drug conjugates. However, the sample size used was small and the duration of exposure to the compound was short. Finally, we do not yet have evidence of how the cells are killed and whether it is truly more active than other antibody-drug conjugates. More specifically, is cell death caused by anti-HER2 binding and activation of antibody-dependent cell-mediated cytotoxicity or is cell death caused by DNA damage due to delivery of the cytotoxic payload? The authors suggest the unique activity of trastuzumab deruxtecan might be related to the high drug-to-antibody ratio and their novel enzymatically cleavable linker, which together might allow for greater delivery of its payload—the cytotoxic chemotherapy. However, given the strong dependency on HER2 expression (or FISH positivity), it is also possible that antibody-dependent cell cytotoxicity plays a role. Aristotle's adage "the more we know, the more we realise we don't know," applies here: although we know that trastuzumab deruxtecan can be given safely to patients, and there is activity in a select group of patients with HER2 positivity (IHC 3+ or FISH-positive), we do not quite know how it kills cancer cells nor do we have confidence in the efficacy of trastuzumab deruxtecan in patients with low HER2 expression. A major issue for any investigator involved in drug development is to address how their drug is uniquely effective. Doi and colleagues discuss this to an extent[2], but thankfully we will have the opportunity to learn more from the expansion cohorts. REFERENCES
DOI: 10.1016/S1470-2045(17)30720-9
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