Choi WonSeok W, Boland Julia L, Kalola Akshar, Lin Jianqing
George Washington University Hospital, Washington DC, USA.
Division of Hematology/Oncology and Department of Medicine, George Washington University School of Medicine and Health Sciences, 2150 Pennsylvania Ave, NW, Suite 1-208, Washington DC, 20037, USA.
Curr Oncol Rep. 2023 Feb;25(2):123-129. doi: 10.1007/s11912-022-01354-5. Epub 2023 Jan 11.
To review the biology, drug development, and clinical data regarding the efficacy and safety of belzutifan (MK-6482), a small molecule inhibitor of HIF-2α.
Belzutifan, a second-generation HIF-2α inhibitor, was shown to provide clinically meaningful benefit in the treatment of VHL-associated tumors (including ccRCC, pancreatic lesions as well as neuroendocrine tumor, and CNS hemangioblastomas). The recommended dose of belzutifan is 120 mg orally daily and half-life is 14 h. In pretreated ccRCC, belzutifan achieved disease control rate of 80% in phase I trial. The most common side effects include anemia and hypoxia related symptoms. Investigation into the important role HIF-2α plays in the expression of genes associated with angiogenesis, erythropoiesis, carcinogenesis, and progression of tumors and the discovery of structural vulnerability within HIF-2α have resulted in the development of a new therapy that has demonstrated efficacy and safety in recent clinical trials. Further research is ongoing to optimize therapeutic benefits from this new exciting therapeutic modality and to improve the outcome of HIF-2α-driven tumors.
综述关于贝佐蒂凡（MK-6482）（一种缺氧诱导因子-2α（HIF-2α）小分子抑制剂）的生物学特性、药物研发以及疗效和安全性的临床数据。
贝佐蒂凡作为第二代HIF-2α抑制剂，在治疗与VHL综合征相关的肿瘤（包括透明细胞肾细胞癌、胰腺病变、神经内分泌肿瘤和中枢神经系统血管母细胞瘤）方面显示出具有临床意义的益处。贝佐蒂凡的推荐剂量为每日口服120毫克，半衰期为14小时。在经预处理的透明细胞肾细胞癌患者中，贝佐蒂凡在I期试验中疾病控制率达到80%。最常见的副作用包括贫血和缺氧相关症状。对HIF-2α在与血管生成、红细胞生成、肿瘤发生和肿瘤进展相关基因表达中所起重要作用的研究，以及对HIF-2α结构脆弱性的发现，促成了一种新疗法的研发，该疗法在近期临床试验中已证明其有效性和安全性。正在进行进一步研究，以优化这种令人振奋的新治疗方式的治疗益处，并改善HIF-2α驱动型肿瘤的治疗效果。
