A ‘game-changer’ for von Hippel-Lindau disease treatment

People with a rare, inherited disorder called von Hippel-Lindau disease develop cancerous and noncancerous tumors in up to 10 different parts of their bodies.

“Having von Hippel-Lindau disease can be overwhelming,” says Eric Jonasch, M.D., who heads MD Anderson’s von Hippel-Lindau Clinic. “Tumors recur frequently throughout your lifetime, and they could only be removed surgically – until now.”

Jonasch led a clinical trial that recently resulted in the Food and Drug Administration’s (FDA’s) approval of the first-ever drug to treat von Hippel-Lindau disease (VHL).

“The drug, belzutifan, is a complete game-changer for patients who have waited decades for an effective treatment,” he says. “Their quality of life is about to dramatically improve.”

Genetic mutation leads to tumor growth

Von Hippel-Lindau disease is caused by a mutation in the VHL gene. Normally, this gene keeps cell growth in check. But when the gene mutates, the gene malfunctions and cells multiply out of control. Masses of cells develop into cancerous and noncancerous tumors in the brain, spine, eyes, ears, lungs, kidneys, pancreas, liver, adrenal glands, and reproductive organs.

As fast as surgeons removed them, new ones appear.

“It’s an endless cat-and-mouse game,” Jonasch says. “We can never predict when or where tumors will show up. Our goal is to stay ahead of them.”

A constant cycle of surveillance, surgery and recovery

To do this, doctors monitor patients from head to toe to identify new tumors and track the growth of existing ones.

“We scan and examine them at least once every two years,” Jonasch says.

When tumors arise, they’re left untouched for a while – the opposite of how most cancers are treated.

“Knowing our patients will develop multiple tumors throughout their lives, we deliberately wait to operate until their tumors grow large enough to damage an organ or spread to other areas,” he explains. “The goal is to control patients’ cancer, and at the same time, spare their organs from the scarring caused by multiple, repeated surgeries. When we do operate, we take out all the possible tumors we can, and leave as much of the organ as possible.” 

This constant cycle of surveillance, surgery and recovery places a tremendous psychological and physical burden on patients, Jonasch says.

“They walk around with the Sword of Damocles hanging over their heads. It’s not an ideal way to live,” he says, “but it’s all they had – until now.”

Clinical trial for von Hippel-Lindau disease

With the FDA’s recent approval of belzutifan, Jonasch expects to see the number of von Hippel-Lindau patients who will need surgery significantly drop.

The FDA approved the drug after a clinical trial involving 61 patients at MD Anderson and 10 other cancer centers produced encouraging results.

The clinical trial was designed to test the drug’s effectiveness in VHL patients who developed a type of kidney cancer called renal cell carcinoma. This is one of the most common cancers in people with von Hippel-Lindau disease. At some point in their lives, about 70% of VHL patients will develop renal cell carcinoma.

After taking belzutifan daily for 18 months, almost half of participants saw their kidney tumors shrink at least 30%.

The drug also shrank tumors in the brain, spine and pancreas.

“Because von Hippel-Lindau disease produces tumors throughout the body, our clinical trial participants had other types of cancer in addition to kidney cancer,” Jonasch says.

91% of pancreatic neuroendocrine tumors (a rare type of pancreatic cancer), and 30% of hemangioblastomas (slow-growing tumors in the brain or spine), shrunk by at least 30%. In a handful of participants, tumors disappeared altogether.

Most participants whose tumors didn’t shrink still got promising news – their tumors stopped growing and remained stable while on belzutifan.

“The drug kept their tumors at bay,” Jonasch says. “When the stable disease numbers are added to the shrinkage numbers, 98% of participants benefited from the medication.”

FDA officials were so impressed by the data that they approved the drug not only for renal cell carcinoma – the original intention of the study – but also for brain and spine hemangioblastomas and pancreatic neuroendocrine tumors.

“Belzutifan fills a huge and previously unmet medical need,” Jonasch says. “This is the first time we have a highly effective medication to treat three types of tumors associated with von Hippel-Lindau disease.”

Side effects were minimal, he says. Some patients experienced none, while others developed anemia, fatigue, headaches and/or dizziness.

“The drug was relatively easy to tolerate,” Jonasch says, “compared to the surgery patients would have needed without it.”

The science behind belzutifan’s success

Belzutifan works by blocking a protein called HIF-2a, which fuels the growth of cancers.

For years, the protein was considered undruggable. It was slippery, and experimental drugs that potentially could have turned off its cancer-promoting action wouldn’t stick to it. But when scientists discovered a tiny pocket on HIF-2a’s surface, they inserted various drug candidates into it and began testing their effectiveness. Eventually, they found a drug that worked. That drug would later become known as belzutifan.

“Patients and their families finally have a reason to hope,” says Jonasch of the discovery of belzutifan. “Most will see their tumors shrink with this new drug, and the cycle of endless surgeries will be broken.”

He points to the 61 clinical trial participants.

“Altogether, the group had an average of 20 surgeries every year before joining the trial. After starting belzutifan, only two needed an operation. The drug nearly eliminates the need for surgery.”

Future research may benefit additional kidney cancer patients

The next step, Jonasch says, is to launch future clinical trials to determine whether belzutifan can help prevent tumors from forming in the first place.

He also wants to know if the drug will be useful in treating other cancers, and he’s already looking at its effect on kidney cancer patients who don’t have VHL disease.

“More than 70,000 people are diagnosed with kidney cancer each year, and most of them don’t have von Hippel-Lindau disease,” Jonasch says. “Their cancers have a very similar genetic makeup to VHL-related kidney cancers. Wouldn’t it be great if the drug works for them, too?”

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