Domb Chaim, Garcia Jorge A, Barata Pedro C, Mendiratta Prateek, Rao Santosh, Brown Jason R
University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
Case Western Reserve University, Cleveland, OH, USA.
Ther Adv Urol. 2024 May 20;16:17562872241249073. doi: 10.1177/17562872241249073. eCollection 2024 Jan-Dec.
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.
抗体药物偶联物和双环毒素偶联物代表了药物递送技术的巨大进步，并在尿路上皮癌的治疗中显示出巨大潜力。先前批准的全身治疗方法，包括化疗和免疫疗法，由于合并症往往不切实际，即使接受全身治疗，晚期疾病患者的预后仍然很差。在这种情况下，抗体药物和双环毒素偶联物已成为新的治疗方法，极大地改变了治疗格局。这些药物采用独特的设计，由抗体或双环肽、连接子和细胞毒性有效载荷组成，比传统化疗具有更有针对性的递送，从而在减少全身毒性的同时消除恶性细胞。在尿路上皮癌中研究的潜在靶点包括Nectin-4、TROP2、HER2和EphA2。初步临床试验证明了其在治疗难治性晚期尿路上皮癌方面的疗效，以及生活质量的改善。这些初步研究导致美国食品药品监督管理局（FDA）批准了两种抗体药物偶联物，即恩杂鲁胺和戈沙妥珠单抗。此外，抗体药物和双环毒素偶联物正在进行的晚期疾病一线治疗以及局部癌症的临床试验中进行研究。这些研究突出了未来利用新靶点、新抗体、细胞毒性和免疫调节有效载荷以及独特结构设计提高疗效和安全性的其他治疗方法的潜力。越来越多的证据表明，与其他癌症治疗方法，尤其是免疫疗法联合使用，可以改善治疗效果。恩杂鲁胺和帕博利珠单抗的联合用药最近被批准用于晚期尿路上皮癌的一线治疗。尽管这些新药前景广阔，但仍需要强大的预测生物标志物来确定将最大程度受益的患者。这篇综述探讨了这些新药的理论基础和当前证据状态，并描述了正在积极探索的未来方向。
