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Abstract：
Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.
Review of recent advances in novel treatments of urothelial cancer Two new types of drugs, called antibody-drug conjugates (ADCs) and bicycle toxin conjugates (BTCs) have shown great promise in treating urothelial cancer. Both types of drugs consist of a structure targeting a specific protein on bladder cancer cells, linked to a drug that can kill cells. This allows for effective treatment of cancer with potentially less toxicity due to the targeted nature of these treatments. We discuss the potential targets in urothelial cancer and the drugs in these classes that could treat each target. Two of these drugs, enfortumab vedotin and sacituzumab govitecan, are in clinical use for cancers that have spread, while the others are in clinical trials. Moreover, the combination of enfortumab vedotin and pembrolizumab, an immunotherapy drug, has excellent results and was recently approved for first-line treatment of urothelial cancer that has spread. Additional studies are looking into these treatments for cancers that have not spread. In the future, management of side effects, determination of which patients benefit, and overcoming when the drugs become no longer effective will be important.
Review of recent advances in novel treatments of urothelial cancer Two new types of drugs, called antibody-drug conjugates (ADCs) and bicycle toxin conjugates (BTCs) have shown great promise in treating urothelial cancer. Both types of drugs consist of a structure targeting a specific protein on bladder cancer cells, linked to a drug that can kill cells. This allows for effective treatment of cancer with potentially less toxicity due to the targeted nature of these treatments. We discuss the potential targets in urothelial cancer and the drugs in these classes that could treat each target. Two of these drugs, enfortumab vedotin and sacituzumab govitecan, are in clinical use for cancers that have spread, while the others are in clinical trials. Moreover, the combination of enfortumab vedotin and pembrolizumab, an immunotherapy drug, has excellent results and was recently approved for first-line treatment of urothelial cancer that has spread. Additional studies are looking into these treatments for cancers that have not spread. In the future, management of side effects, determination of which patients benefit, and overcoming when the drugs become no longer effective will be important.
摘要：
抗体-药物缀合物和双环毒素缀合物代表了药物递送技术的巨大进步，并在治疗尿路上皮癌方面显示出巨大的前景。以前批准的全身疗法，包括化疗和免疫疗法，通常由于合并症而不切实际，晚期疾病患者的预后仍然很差，即使在接受全身治疗时。在此设置中，抗体-药物和自行车毒素缀合物已经成为新的治疗方法，戏剧性地改变了治疗环境。这些药物利用独特的设计，包括抗体或自行车肽，连接体,和细胞毒性有效载荷比传统化疗更具靶向性，从而消除恶性细胞，同时减少全身毒性。在尿路上皮癌中研究的潜在靶标包括Nectin-4、TROP2、HER2和EphA2。最初的临床试验证明了治疗难治性晚期尿路上皮癌的疗效，以及生活质量的提高。这些初步研究导致FDA批准了两种抗体-药物缀合物，enfortumabvedotin和sacituzumabgovitecan。此外，抗体-药物和自行车毒素缀合物正在进行的临床试验中研究，用于晚期疾病和局部癌症的一线治疗。这些研究强调了具有新靶标的其他未来疗法的潜力，新型抗体，细胞毒性和免疫调节有效载荷，和独特的结构设计增强功效和安全性。越来越多的证据表明，与其他癌症疗法的组合，特别是免疫疗法，改善治疗结果。enfortumabvedotin和pembrolizumab的组合最近被批准用于晚期尿路上皮癌的一线治疗。尽管这些新药大有可为,需要稳健的预测性生物标志物来确定哪些患者将获得最大益处.这篇综述调查了这些新药证据的基本原理和现状，并描述了未来正在积极探索的方向。
综述尿路上皮癌新型治疗方法的最新进展两种新型药物，被称为抗体-药物缀合物（ADC）和双环毒素缀合物（BTC）在治疗尿路上皮癌方面显示出巨大的前景。这两种类型的药物都由靶向膀胱癌细胞上特定蛋白质的结构组成，与可以杀死细胞的药物有关。由于这些治疗的靶向性质,这允许以潜在较低的毒性有效治疗癌症。我们讨论了尿路上皮癌的潜在靶标以及这些类别中可以治疗每个靶标的药物。其中两种药物,enfortumabvedotin和sacituzumabgovitecan，临床上用于已经扩散的癌症，而其他人正在临床试验中。此外，enfortumabvedotin和pembrolizumab的组合，一种免疫治疗药物，具有优异的效果，最近被批准用于已经扩散的尿路上皮癌的一线治疗。其他研究正在研究这些尚未扩散的癌症的治疗方法。在未来,副作用的管理，确定哪些患者受益，和克服当药物变得不再有效将是重要的。
综述尿路上皮癌新型治疗方法的最新进展两种新型药物，被称为抗体-药物缀合物（ADC）和双环毒素缀合物（BTC）在治疗尿路上皮癌方面显示出巨大的前景。这两种类型的药物都由靶向膀胱癌细胞上特定蛋白质的结构组成，与可以杀死细胞的药物有关。由于这些治疗的靶向性质,这允许以潜在较低的毒性有效治疗癌症。我们讨论了尿路上皮癌的潜在靶标以及这些类别中可以治疗每个靶标的药物。其中两种药物,enfortumabvedotin和sacituzumabgovitecan，临床上用于已经扩散的癌症，而其他人正在临床试验中。此外，enfortumabvedotin和pembrolizumab的组合，一种免疫治疗药物，具有优异的效果，最近被批准用于已经扩散的尿路上皮癌的一线治疗。其他研究正在研究这些尚未扩散的癌症的治疗方法。在未来,副作用的管理，确定哪些患者受益，和克服当药物变得不再有效将是重要的。
