Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease

被引:442
作者
Jonasch, Eric [1 ]
Donskov, Frede [2 ]
Iliopoulos, Othon [3 ,4 ]
Rathmell, W. Kimryn [5 ]
Narayan, Vivek K. [6 ]
Maughan, Benjamin L. [7 ]
Oudard, Stephane [8 ]
Else, Tobias [9 ]
Maranchie, Jodi K. [10 ]
Welsh, Sarah J. [11 ]
Thamake, Sanjay [12 ]
Park, Eric K. [12 ]
Perini, Rodolfo F. [12 ]
Linehan, W. Marston [13 ]
Srinivasan, Ramaprasad [13 ,14 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
[2] Aarhus Univ Hosp, Aarhus, Denmark
[3] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA
[4] Harvard Med Sch, Boston, MA 02115 USA
[5] Vanderbilt Univ, Med Ctr, Nashville, TN USA
[6] Univ Penn, Philadelphia, PA 19104 USA
[7] Univ Utah, Salt Lake City, UT USA
[8] Univ Paris, Hop Europeen Georges Pompidou, Paris, France
[9] Univ Michigan, Ann Arbor, MI 48109 USA
[10] Univ Pittsburgh, Pittsburgh, PA USA
[11] Cambridge Univ Hosp NHS Fdn Trust, Cambridge, England
[12] Merck, Kenilworth, NJ USA
[13] NCI, Ctr Canc Res, Bethesda, MD 20892 USA
[14] NCI, Ctr Canc Res, Mol Canc Sect, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA
关键词
ANTAGONIST; TRIAL; VHL;
D O I
10.1056/NEJMoa2103425
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background 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 2 alpha (HIF-2 alpha). Methods In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2 alpha 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. Results 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). Conclusions 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, .) HIF-2 alpha Inhibition in von Hippel-Lindau Disease The cause of von Hippel-Lindau disease is excess activity of the HIF-2 alpha pathway. A total of 61 patients with renal cell carcinoma and other proliferative manifestations of the hypoxia-induced signaling pathway received belzutifan, which inhibits the HIF-2 alpha pathway. Nearly half the patients with renal cell carcinoma had a response to treatment, and 98% had disease control.
引用
收藏
页码:2036 / 2046
页数:11
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