Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland.
Clin Cancer Res. 2022 Nov 14;28(22):4843-4848. doi: 10.1158/1078-0432.CCR-22-1054.
On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.
2021 年 8 月 13 日，FDA 批准贝伐珠单抗（WELIREG，默克公司）用于治疗需要治疗相关肾细胞癌（RCC）、中枢神经系统（CNS）血管母细胞瘤或胰腺神经内分泌肿瘤（pNET）的 von Hippel-Lindau（VHL）病成年患者，这些患者存在缺氧诱导因子（HIF）抑制剂类药物首选用药指征。FDA 的批准是基于在参与 MK-6482-004 研究的患者中观察到的对总缓解率（ORR）具有临床意义的影响。所有 61 名患者均患有 VHL 相关性 RCC；部分患者还患有 CNS 血管母细胞瘤和/或 pNET。对于 VHL 相关性 RCC，ORR 为 49%（95%置信区间[CI]，36-62%），中位缓解持续时间（DoR）未达到，56%的缓解者 DoR≥12 个月，中位反应时间为 8 个月。24 名患者的 CNS 血管母细胞瘤可测量，ORR 为 63%（95%CI，41-81%），12 名患者的 pNET 可测量，ORR 为 83%（95%CI，52-98%）。对于这些肿瘤，中位 DoR 未达到，CNS 血管母细胞瘤和 pNET 患者分别有 73%和 50%的患者缓解持续时间≥12 个月。报告发生率≥20%的最常见不良反应（包括实验室异常）为贫血、疲劳、肌酐升高、头痛、头晕、血糖升高和恶心。贝伐珠单抗可使一些激素避孕药无效，并可在怀孕期间对胚胎造成伤害。本文总结了支持 FDA 批准贝伐珠单抗用于该适应证的相关数据和思维过程。
