Mukohara Toru
Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Expert Opin Pharmacother. 2025 May;26(7):791-799. doi: 10.1080/14656566.2025.2488456. Epub 2025 Apr 9.
The treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been improved through the development of endocrine therapy (ET) and targeted agents. However, resistance to ET, particularly caused by mutations, has not been fully addressed.
Vepdegestrant is a first-in-class, selective, and orally bioavailable PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. Preclinical studies have suggested promising activity of vepdegestrant irrespective of genotypes. Phase I and II clinical studies have revealed a favorable safety profile and encouraging efficacy of vepdegestrant as a single agent and in combination with other targeted agents.
The results of the phase III VERITAC-2 study, comparing vepdegestrant with fulvestrant, are expected to be available in 2025, and will provide the first data on the true clinical significance of vepdegestrant. Several phase III studies of combinations with vepdegestrant including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) have been or are planned to be conducted. The results of these may not only transform the treatment landscape for advanced HR+/HER2- breast cancer but may pave the way for PROTAC as a new class of anti-cancer drugs that may make previously undruggable targets druggable.
通过内分泌治疗（ET）和靶向药物的发展，晚期激素受体阳性（HR+）和人表皮生长因子受体2阴性（HER2-）乳腺癌的治疗已经得到改善。然而，对ET的耐药性，特别是由突变引起的耐药性，尚未得到充分解决。
维泊妥珠单抗是一流的、选择性的、口服生物可利用的蛋白水解靶向嵌合体（PROTAC）雌激素受体（ER）降解剂。临床前研究表明，无论基因型如何，维泊妥珠单抗都具有有前景的活性。I期和II期临床研究显示，维泊妥珠单抗作为单一药物以及与其他靶向药物联合使用时，具有良好的安全性和令人鼓舞的疗效。
比较维泊妥珠单抗与氟维司群的III期VERITAC-2研究结果预计将于2025年公布，并将提供关于维泊妥珠单抗真正临床意义的首批数据。几项关于维泊妥珠单抗联合用药的III期研究，包括与阿替利西利布（一种细胞周期蛋白依赖性激酶4抑制剂）联合，已经或计划进行。这些研究结果不仅可能改变晚期HR+/HER2-乳腺癌的治疗格局，而且可能为PROTAC作为一类新的抗癌药物铺平道路，这类药物可能使以前难以成药的靶点变得可成药。
