Approval of belzutifan for treatment of kidney cancers and other neoplasms associated with von Hippel-Lindau (VHL) syndrome is being hailed by medical specialists as a major advance in the management of this difficult-to-manage disease.

The Food and Drug Administration approved belzutifan based on a phase 2, open-label, single-arm trial demonstrating that treatment with belzutifan, a small-molecule inhibitor of hypoxia-inducible factor 2α (HIF-2α), had strong clinical activity in patients with renal cell carcinoma (RCC) and non-RCC neoplasms associated with VHL disease. The study, which was published in the New England Journal of Medicine, suggests this agent may be an effective systemic alternative that can help reduce the surgical burden in patients with VHL disease.

‘Ushers in a New Era’

Continue Reading

“Belzutifan ushers in a new era for patients with VHL syndrome,” said Arnab Basu, MD, an assistant professor in the division of hematology/oncology at the University of Alabama in Birmingham. “These patients, often very young, suffer from disabling symptoms related to tumors that involve the spine, brain, pancreas, retina, and kidneys. While there were some treatments for kidney cancer, the other VHL-related tumors did not respond well.”

Belzutifan may be able to help patients achieve a better quality of life, as this therapy could potentially delay or avoid the need for surgery, Dr Basu said. VHL follows an autosomal dominant inheritance pattern, in which inheriting 1 copy of the altered gene will likely result in a mutation of the second (normal) copy of the gene. This elevates the risk for cancer development. “These previously refractory tumors are now responding, with 100% of patients with retinal lesions, and 77% of patients with pancreatic lesions having significant improvement when treated with belzutifan,” Dr Basu said.

An additional benefit of the drug appears to be its excellent tolerability, with anemia and fatigue as the most common side effects. “The anemia is easily manageable through erythropoietin replacement,” Dr Basu said. “We are looking forward to further confirmatory studies in kidney cancers and other disease types.”

Impressive Response Rates

Niraj Shenoy, MD, PhD, an associate professor of medicine in the division of hematology/oncology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, called the drug “an important and exciting advance for patients with VHL disease-associated malignancies due to the impressive response rates and manageable adverse effects reported.” 

He added, “That said, careful patient selection, monitoring, and appropriate management of adverse effects will be important to ensure a favorable clinical benefit/adverse effect profile for most patients. We will learn more about the drug in the post-approval, real-world setting over the next few years.”  

In the study, the objective response rate (ORR) in patients with RCC was 49% after a median follow-up of 21.8 months, with 92% of patients experiencing a decrease in the sum of all target lesion diameters, Eric Jonasch, MD, professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston, and colleagues reported. Progression-free survival was 96% at 24 months.

“We were pleasantly surprised to see a high rate of response in other VHL disease manifestations, including a 91% ORR in pancreatic neuroendocrine tumors, and a 30% ORR in hemangioblastomas,” Dr Jonasch said in an interview.

Loss of VHL function results in the cell’s inability to down regulate HIF-2a, a transcription factor, with resultant inappropriate transcription of a number of proangiogenic, metabolic and prosurvival genes leading to tumor development. Inactivation of the VHL tumor-suppressor protein also occurs in more than 90% of sporadic RCC tumors. Belzutifan directly targets HIF-2a, hindering cancer cell growth and abnormal blood vessel development. “The favorable toxicity profile of belzutifan points to its specificity,” Dr Jonasch explained.

Originally known as MK-6482, belzutifan was approved by the FDA on Aug. 13, 2021 based on previous results in this trial. The trial included 61 patients from 11 centers in the United States, Denmark, France, and the United Kingdom. All patients had a germline mutation diagnosis of VHL disease, measurable non-metastatic RCC tumors, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received prior systemic cancer therapy. Patients’ median age was 41 years (range 19 to 66 years), 52% were men, and 82% had an ECOG performance-status score of 0. Almost the entire cohort (97%) had undergone at least 1 previous tumor reduction procedure, such as partial nephrectomy, craniotomy, or cryoablation.

Belzutifan was administered orally at a dosage of 120 mg once daily and tumor size was evaluated at screening and then every 12 weeks. No patients had progressive disease on treatment. Treatment was ongoing in 54 patients (89%) at the time of data cutoff. The most common adverse events were anemia (90%) and fatigue (66%). No deaths occurred from a treatment-related adverse event. However, 7 patients discontinued treatment and 1 patient died from acute toxic effects of fentanyl.

“The main side effects included the on-target induction of anemia, as HIF-2α is the transcription factor for erythropoietin, as well as mild hypoxia,” Dr Jonasch said. “The mechanism of hypoxia induction is unclear, but is managed with dose interruption/reduction where necessary.”

Responses occurred in 77% of patients with VHL-associated pancreatic lesions and 30% of patients with VHL-associated central nervous system hemangioblastomas. Among the 12 patients with retinal hemangioblastomas at baseline, 100% were graded as showing improvement. The median time to response was 8.2 months (range 2.7 to 19.1 months).

The authors noted the trial is limited by its small sample size and a lack of a control group. Neoplasms associated with VHL disease, however, are currently only managed with surgical resection or ablation to reduce metastatic disease risk and for controlling local or systemic sequelae, they pointed out.


Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau Disease. N Engl J Med.2021;385:2036-46. doi:10.1056/NEJMoa2103425