From the University of Texas M.D. Anderson Cancer Center, Houston (E.J.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (O.I.); Vanderbilt University Medical Center, Nashville (W.K.R.); University of Pennsylvania, Philadelphia (V.K.N.); the University of Utah, Salt Lake City (B.L.M.); Hôpital Européen Georges-Pompidou, University of Paris, Paris (S.O.); the University of Michigan, Ann Arbor (T.E.); the University of Pittsburgh, Pittsburgh (J.K.M.); Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom (S.J.W.); Merck, Kenilworth, NJ (S.T., E.K.P., R.F.P.); and the Center for Cancer Research, National Cancer Institute, Bethesda, MD (W.M.L., R.S.).
N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425.
Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to 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.).
由于基因失活和转录因子缺氧诱导因子 2α（HIF-2α）的组成性激活，患有 von Hippel-Lindau（VHL）病的患者肾细胞癌的发生率很高。
在这项 2 期、开放标签、单组试验中，我们研究了 HIF-2α抑制剂贝鲁替尼（MK-6482，以前称为 PT2977）在 VHL 相关肾细胞癌患者中的疗效和安全性，每日口服 120mg。主要终点是根据实体瘤反应评估标准，1.1 版（RECIST v1.1），由独立的中央放射学审查委员会评估的客观反应（完全或部分反应）。我们还评估了贝鲁替尼对非肾细胞癌肿瘤的反应和贝鲁替尼的安全性。
中位随访 21.8 个月（范围，20.2 至 30.1）后，肾细胞癌患者的客观反应率为 49%（95%置信区间，36 至 62）。在胰腺病变患者（61 例中有 47 例[77%]）和中枢神经系统血管母细胞瘤患者（50 例中有 15 例[30%]）中也观察到了反应。在基线时有 12 例视网膜血管母细胞瘤的 16 只眼中，所有（100%）均被评为改善。最常见的不良事件是贫血（90%的患者）和疲劳（66%）。有 7 名患者停止治疗：4 名患者自愿停药，1 名因治疗相关不良事件（1 级头晕）停药，1 名因研究者评估的疾病进展而停药，1 名患者死亡（芬太尼的急性毒性作用）。
贝鲁替尼与主要为 1 级和 2 级不良事件相关，并在患有 VHL 相关肾细胞癌和非肾细胞癌肿瘤的患者中显示出活性。（由默克公司和其他人资助；MK-6482-004 临床试验.gov 编号，NCT03401788）。
