Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.
Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.
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DOI：
10.1056/nejmoa2103425
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发表时间：
2021-11-25
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由于von Hippel-Lindau病基因失活和转录因子低氧诱导因子2α(HIF-2α)的结构性激活，导致肾细胞癌的发生率较高。在这项第二阶段的开放标签单组试验中，我们研究了低氧诱导因子-2α抑制剂belzutifan(MK-6482，以前称为PT2977)对肾癌患者的疗效和安全性。主要终点是客观反应(完全或部分反应)，根据独立的中央放射学审查委员会根据实体肿瘤反应评估标准1.1版进行测量。我们还评估了非肾细胞癌患者对Belzutifan的反应和Belzutifan的安全性。经过平均21.8个月(20.2至30.1)的随访，肾细胞癌患者的客观有效率为49%(95%可信区间为36至62)。胰腺病变(61例患者中47例(77%))和中枢神经系统血管母细胞瘤(50例患者中15例(30%))也观察到了反应。在12例视网膜血管母细胞瘤患者的16只眼中，所有患者(100%)均为改善。最常见的不良反应是贫血(90%的患者)和疲劳(66%)。7名患者停止治疗：4名患者自愿停止治疗，1名患者因与治疗相关的不良事件(1级头晕)而停止治疗，1名患者因研究人员评估的疾病进展而停止治疗，1名患者死亡(死于芬太尼的急性毒性反应)。Belzutifan主要与1级和2级不良反应有关，并在与VHL疾病相关的肾细胞癌和非肾细胞癌患者中表现出活性。(由默克·夏普和多姆等人资助；MK-6482-004 ClinicalTrials.gov编号，NCT03401788。)
Patients with von Hippel–Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non–renal cell carcinoma neoplasms and the safety of belzutifan. After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non–renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.)