TY - JOUR
T1 - Belzutifan for renal cell carcinoma in von Hippel-Lindau disease
AU - the MK-6482-004 Investigators
AU - Jonasch, Eric
AU - Donskov, Frede
AU - Iliopoulos, Othon
AU - Rathmell, W. Kimryn
AU - Narayan, Vivek K.
AU - Maughan, Benjamin L.
AU - Oudard, Stephane
AU - Else, Tobias
AU - Maranchie, Jodi K.
AU - Welsh, Sarah J.
AU - Thamake, Sanjay
AU - Park, Eric K.
AU - Perini, Rodolfo F.
AU - Linehan, W. Marston
AU - Srinivasan, Ramaprasad
N1 - Funding Information:
Supported by Merck Sharp and Dohme, a subsidiary of Merck; the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) Center for Cancer Research; and a grant (UO1 CA236489) from the NCI.
Publisher Copyright:
Copyright © 2021 Massachusetts Medical Society.
PY - 2021/11/25
Y1 - 2021/11/25
N2 - 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 2α (HIF-2α). METHODS 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. 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.
AB - 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 2α (HIF-2α). METHODS 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. 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.
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U2 - 10.1056/NEJMoa2103425
DO - 10.1056/NEJMoa2103425
M3 - Article
C2 - 34818478
AN - SCOPUS:85120497302
SN - 0028-4793
VL - 385
SP - 2036
EP - 2046
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 22
ER -