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Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease
Eric Jonasch1, Frede Donskov1, Othon Iliopoulos1
1From 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.).
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. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).
Insights
Belzutifan, a hypoxia-inducible factor 2α inhibitor, demonstrated efficacy in treating renal cell carcinoma and other neoplasms in patients with von Hippel-Lindau disease. The treatment showed notable response rates with manageable side effects.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Von Hippel-Lindau (VHL) disease is linked to high rates of renal cell carcinoma due to VHL gene inactivation.
- This inactivation leads to the overactivation of hypoxia-inducible factor 2α (HIF-2α).
Purpose of the Study:
- To investigate the efficacy and safety of belzutifan, an HIF-2α inhibitor, in patients with VHL disease-associated renal cell carcinoma.
- To assess belzutifan's effects on non-renal cell carcinoma neoplasms and its overall safety profile.
Main Methods:
- A phase 2, open-label, single-group trial was conducted.
- Patients received oral belzutifan at 120 mg daily.
- Objective response was the primary endpoint, assessed by independent central radiology review.
Main Results:
- An objective response rate of 49% was observed in patients with renal cell carcinoma after a median follow-up of 21.8 months.
- Significant responses were also seen in pancreatic lesions (77%) and central nervous system hemangioblastomas (30%).
- Adverse events were predominantly grade 1 and 2, with anemia (90%) and fatigue (66%) being most common.
Conclusions:
- Belzutifan demonstrated activity in treating renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease.
- The drug was generally well-tolerated, with predominantly mild to moderate adverse events.
- Belzutifan represents a potential therapeutic option for VHL disease-related tumors.
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