Department of Medical Oncology, IRCCS San Raffaele Hospital, Milano, Italy.
Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS San Raffaele Hospital, Milan, Italy.
Urol Oncol. 2022 Oct;40(10):413-423. doi: 10.1016/j.urolonc.2022.07.006. Epub 2022 Aug 13.
Metastatic urothelial cancer (mUC) is an aggressive disease with limited overall survival and treatment options. Antibody-drug conjugates (ADCs) were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to monoclonal antibodies (mAbs) and have emerged as new treatment options in mUC, mainly in chemotherapy (CT) and immune-checkpoint inhibitors (ICI)-exposed patients. We aimed to perform a scoping review to assess activity, efficacy, treatment-related adverse events (TRAEs), and impact on quality of life of ADCs in mUC.
A review of the literature was performed in January 2022 using Pubmed and Embase databases according to the recommendations of the Joanna Briggs Institute. The search method involved querying for the terms "bladder carcinoma" or "urothelial carcinoma" with any of the following: "enfortumab vedotin" (EV), "sacituzumab govitecan" (SG), antibody-drug conjugate. Only prospective clinical trials were included.
Ultimately, eleven clinical trials with 1417 patients were selected for inclusion, and five drugs were identified: enfortumab vedotin (EV), sacituzumab govitecan (SG), disitamab vedotin (RC48-ADC), ASG-15ME (anti-SLITRK6), and trastuzumab deruxtecan. The different ADCs have been tested mainly in phase 1 or phase 2 trials, as monotherapy or in combination with ICI. Response rate ranged from 27% with SG in previously treated patients to 73.3% with EV plus pembrolizumab in cisplatin-ineligible patients as first-line treatment. The phase 3 trial, EV-301, confirmed EV superiority over investigator-chosen CT after failure to platinum-based CT and ICI, improving overall survival (12.88 vs. 8.97 months; HR 0.70; 95% CI, 0.56-0.89; P=0.001). TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of grade 3 ≥ events ranging from 51.4 to 73.5% in different trials. TRAEs of particular interest related to EV were rash, neuropathy, and hyperglycemia. SG was associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life but an improvement in pain symptoms compared to the control arm.
ACDs represent a new therapeutic option for the treatment of mUC. Level-1 evidence has already been achieved by EV in the post-CT and post-ICI settings. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Clinicians should be aware of possible adverse events and their optimal management.
转移性尿路上皮癌（mUC）是一种侵袭性疾病，总生存时间有限，治疗选择有限。抗体药物偶联物（ADC）旨在通过将细胞毒素连接到单克隆抗体（mAbs）上来选择性地将有效细胞毒素递送至表达抗原的肿瘤细胞，已成为 mUC 的新治疗选择，主要在化疗（CT）和免疫检查点抑制剂（ICI）暴露的患者中。我们旨在进行范围审查，以评估 ADC 在 mUC 中的活性、疗效、与治疗相关的不良事件（TRAEs）以及对生活质量的影响。
根据乔安娜·布里格斯研究所的建议，于 2022 年 1 月在 Pubmed 和 Embase 数据库中进行文献综述。搜索方法涉及用“膀胱癌”或“尿路上皮癌”查询与以下任何一项相关的术语：“enfortumab vedotin”（EV）、“sacituzumab govitecan”（SG）、抗体-药物偶联物。仅纳入前瞻性临床试验。
最终，纳入了 11 项包含 1417 名患者的临床试验，确定了 5 种药物：enfortumab vedotin（EV）、sacituzumab govitecan（SG）、disitamab vedotin（RC48-ADC）、ASG-15ME（抗 SLITRK6）和 trastuzumab deruxtecan。不同的 ADC 主要在 1 期或 2 期试验中作为单药或与 ICI 联合进行测试。反应率从 SG 在先前治疗的患者中为 27%到 EV 加 pembrolizumab 在顺铂不耐受患者中作为一线治疗为 73.3%不等。EV-301 三期试验证实了 EV 在铂类 CT 和 ICI 失败后优于研究者选择的 CT，改善了总生存期（12.88 与 8.97 个月；HR 0.70；95%CI，0.56-0.89；P=0.001）。在 2 期或 3 期试验中，任何等级的 TRAEs 均发生在超过 90%的患者中，不同试验中 3 级≥事件的发生率为 51.4%至 73.5%。与 EV 相关的特别关注的 TRAEs 包括皮疹、神经病变和高血糖。SG 与腹泻和血液学毒性相关。EV 的 2 期和 3 期试验数据表明，与对照组相比，它对生活质量没有影响，但可改善疼痛症状。
ADC 是治疗 mUC 的一种新的治疗选择。EV 在 CT 后和 ICI 后环境中已获得 1 级证据。在 2 期和 3 期试验中观察到高发生率的潜在不良事件，包括皮疹、中性粒细胞减少症、血液学毒性和神经病变。临床医生应了解可能出现的不良事件及其最佳管理方法。
