An exciting new study has just been published looking at a potential new drug to treat von-Hippel-Lindau (VHL) disease. Here, we describe the study and discuss what this may mean for Birt-Hogg-Dubé Syndrome (BHD), which has similarities with VHL.

VHL is a rare genetic disorder, caused by mutations in the VHL gene. Around 7 in 10 people with VHL develop kidney cancer and need multiple surgeries during their lifetime. A drug that can reduce the size of, or completely remove tumours could prevent the need for surgery. 

The VHL protein regulates the activity of another protein called hypoxia-inducible factor (HIF), which is involved in our response to low oxygen conditions. When oxygen levels are normal, VHL will act to stop the activity of HIF. However, when oxygen levels are low, the HIF protein becomes active. This stimulates the formation of blood vessels to help increase the flow of oxygen into our tissues When VHL is mutated, is loses the ability to control HIF, which is then in a permanently “on” state, even with normal oxygen levels. In VHL kidney cancer, the tumours often have more blood vessels. This is thought to be a result of uncontrolled HIF activity. If a drug were able to stop HIF activity in kidney cancer it would represent an exciting new therapy for patients with VHL.

Jonasch et al., wanted to test this theory using a drug called Belzutifan, which inhibits the activity of HIF. This drug has already shown some effect in clear-cell kidney cancer. In a clinical trial (a controlled way to test if a drug is working in humans), they tested the activity of this drug in VHL patients with kidney cancer.

How did the trial work? 

61 patients with VHL disease entered the trial. Patients were all over 18 years old, with at least one kidney cancer tumour bigger than 1cm. Patients were not allowed to join if they had tumours over 3cm in diameter, as these would require surgery. Patients with cancer which had spread to other areas were not allowed to take part.

Treatment 

Patients were given the drug as a tablet orally once a day. Patients left the study if the drug produced unacceptable side effects, or the cancer continued to progress. The researchers looked at the effect of the drug in each patient after 21.8 months on average.

Results  

30 of the 61 patients showed a reduction in the size of their tumours (termed a partial response). Another 30 patients showed no progression of the cancer in this time period (termed stable disease). One patient left the trial before the first measurements were taken. 

Safety 

Side effects are common with all drugs, and all patients experienced at least one side effect. The most common side effects were anaemia (low red blood cell count), fatigue (unusual tiredness not related to activity), headache and dizziness. Only one patient stopped taking the drug due to side effects.

Discussion 

Belzutifan is a potential new drug for the management of VHL kidney cancer. As in BHD, when tumours reach 3 cm in diameter in VHL disease, they are surgically removed. A drug that can reduce the size of, or completely remove any tumours is likely to result in fewer surgeries. On average, the patients in this trial had already had 4 previous surgical procedures. Interestingly, only 3 of the patients in the study needed surgery since it began. These results show the drug worked well in VHL kidney cancer, was safe and the side effects were well tolerated. More work needs to be done to see when the best time to take this drug would be, and how it would benefit patients.

The BHD Foundation are very excited by the results of this trial. Folliculin, the gene mutated in BHD, is also known to activate HIF. It may be possible that belzutifan could have some benefits for individuals with BHD. To find out more, we spoke to one of the researchers involved in the trial and BHD expert Dr Marston Linehan (National Cancer Institute, NIH). 

Why is another approach for kidney cancer management needed for individuals with VHL disease? 

The reason we worked on the development of a treatment for VHL kidney cancer over the past 38 years is so that we would have an alternative to surgery for these patients and could delay or completely prevent kidney tumor development.

What are the next steps for taking belzutifan from clinical trials to approved use in patients with VHL disease? 

We still have many questions to answer such as:

• When is the optimal time to prescribe the agent for VHL-associated renal tumors?
• How long is the optimal time period to give the agent in patients with VHL-associated kidney tumors?
• We need to identify the causes of tumor resistance to therapy.

What can we learn from this trial to look at potential treatments for BHD? 

• We can learn about the potential for targeted systemic agents in patients with genetically defined, inherited forms of kidney cancer such as BHD.
• Also, although we worked towards the development of agents targeting the VHL pathway to treat kidney cancer, in the belzutifan trial we learned that this agent also has activity in treating central nervous system tumors (CNS hemangioblastomas) and pancreatic neuroendocrine tumors.
• As we have worked on the development of a therapeutic approach for the treatment of tumors in patients affected with BHD over the past 25 years, it is our hope that when we see the development of an effective approach to target the FLCN (BHD gene) pathway that we will see effect on not only the BHD-associated kidney tumors, but also on BHD-associated pulmonary cysts and cutaneous fibrofolliculomas.
• We have a way to go, however, we are encouraged by the progress that has been made.

Do you think this approach is the future for management of BHD?

Yes, I do feel that this is the future for the management of BHD.  This was our goal, our “vision”, when we started on VHL in the early 1980’s.  It was also our goal when we started working on BHD in the mid 1990’s.  We will not stop until we have seen the development of effective forms of treatment for all patients affected with BHD and VHL, as well as those affected with Hereditary Papillary Kidney Cell Carcinoma (starting in 1991), Hereditary Leiomyomatosis and Kidney Cell Carcinoma (HLRCC) (starting in 1989) and TFE3, TFEB and MITF kidney cell carcinoma (starting in 1987).

We are very appreciative of the support and encouragement of the Myrovlytis Trust and of the brave and courageous BHD patients who have made it possible for us to make the progress we have over the past 25 years.  We are optimistic about the future. 

The BHD Foundation are extremely thankful to Dr Marston Linehan for his time and his passion and work on BHD and other hereditary kidney cancers.