HomeLifestyleHealth & FitnessBelzutifan elicits strong responses in VHL-associated kidney cancer patients

Belzutifan elicits strong responses in VHL-associated kidney cancer patients

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Von Hippel-Lindau patients are at risk of developing many cancers and require frequent surgery to treat their tumors. These findings fundamentally change how we treat patients with VHL disease, and will benefit the vast majority of patients.

Using belzutifan, a small-molecule inhibitor of hypoxia-inducible factor (HIF)-2a, researchers at the University of Texas MD Anderson Cancer Center demonstrated clinical activity in patients with RCC and non-RCC neoplasms associated with von Hippel-Lindau disease. 

After a median follow-up of 21.8 months, the objective response rate in patients with RCC was 49 percent. Additionally, 92% of patients had a reduction in the size of their targeted lesions. At 24 months, 96 percent of patients remained progression-free.

The Food and Drug Administration authorized Belzutifan, formerly known as MK-6482, on Aug. 13, 2021, based on previously released study data. It is the first therapy for VHL disease to be approved by the FDA.

“Patients with von Hippel-Lindau disease are at risk of developing several types of cancer and require repeated surgical procedures to manage their tumors,” says principal investigator Eric Jonasch, M.D., professor of Genitourinary Medical Oncology.

“These results profoundly change the way we manage patients with VHL disease and will provide an impactful benefit to a majority of patients with VHL.”

VHL disease is caused by an extremely rare hereditary mutation in the VHL gene and is associated with several organ cancers. Although some of these tumors are benign, they can grow and cause organ damage. Additionally, VHL might result in malignant tumors in the kidney or pancreas. RCC occurs in around 40% of people with VHL illness and is one of the leading reasons of death in these patients.

The VHL mutation impairs cells’ capacity to respond appropriately to changes in oxygen levels, resulting in an accumulation of HIF proteins. This process wrongly informs the cells that they are oxygen-deprived, resulting in the development of blood vessels and tumor growth. VHL tumor-suppressor protein inactivation is also present in more than 90% of sporadic RCC tumors. Belzutifan acts directly on HIF-2a, preventing cancer cells from growing, spreading, and developing aberrant blood vessels.

Active surveillance is used to treat VHL disease-associated kidney malignancies until surgery is required to prevent metastatic disease in tumors larger than 3 cm. Repeated surgical operations can be extremely dangerous, as many individuals develop renal insufficiency. Surgery is not designed to cure VHL illness in individuals with RCC, but rather to prevent death from metastatic kidney cancer.

“Half of the patients in this trial had an objective response and almost all patients saw a decrease in the size of their lesions,” Jonasch adds. “Patients with VHL are able to have a better quality of life as this therapy can delay or avoid the need for surgery.”

61 patients were enrolled in the single-arm clinical trial at 11 sites in the United States, Denmark, France, and the United Kingdom. Adult patients with a hereditary VHL disease diagnosis, no prior systemic cancer therapy, detectable non-metastatic RCC tumors, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were enrolled in the trial.

Belzutifan was given to patients once a day until disease progression, unacceptable toxicity, or withdrawal. The size of the tumor was measured during screening and then every 12 weeks after that. There were no patients who developed progressive disease while on treatment, and 54 patients (89 percent) are still on it.

The majority of treatment-related adverse events (AEs) were of grade 1 or 2. Anemia (90 percent) and tiredness were the most common side effects (66 percent ). A treatment-related adverse event did not result in any deaths.

VHL-related pancreatic lesions elicited responses in 77 percent of patients, whereas VHL-related central nervous system hemangioblastomas elicited responses in 30 percent of patients. The 12 patients who had retinal hemangioblastomas at the start of the study were all classified as improving.

“These data suggest HIF-2a inhibition offers an effective treatment option with manageable side effects for patients with VHL-associated renal cell carcinoma and other VHL-related tumors,” Jonasch says.

“I am excited to be able to provide this impactful therapy to patients who have waited a long time for new options.”

The lack of a control group and the small sample size limit the trial. Designing a randomized controlled study is an ethical difficulty, according to Jonasch, because there are no recognized nonsurgical therapy options for VHL disease. Future research may look into whether this treatment will help people with VHL disease avoid developing new lesions.

Source: 10.1056/NEJMoa2103425

Image Credit: iStock

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