At the VHL Alliance, we are committed to bringing you the latest developments in research and treatment options for Von Hippel-Lindau (VHL) disease. Managing VHL can be challenging, but recent studies on a medication called Belzutifan are providing new hope. Here, we share some exciting findings from recent research on Belzutifan and what they could mean for you and your loved ones.
Belzutifan: A Promising Treatment for VHL
Belzutifan is a medication that targets a protein known as hypoxia-inducible factor 2-alpha (HIF-2α), which plays a key role in the growth of VHL-related tumors. By blocking this protein, Belzutifan helps slow down or even shrink tumors, offering a new way to manage VHL disease without invasive surgeries or other aggressive treatments. Below, we summarize the key findings from several recent studies that explored how Belzutifan can help patients with VHL disease.
Finding the Right Dose of Belzutifan
The LITESPARK-013 study is a phase 2 clinical trial that compared two doses of Belzutifan (120 mg and 200 mg) in patients with advanced clear cell renal cell carcinoma (ccRCC) whose disease had progressed after prior systemic therapies, including programmed death receptor (or ligand)-1 (PD-(L)1) inhibitors. The primary goal was to determine if a higher dose would offer greater efficacy without increasing adverse effects, thus optimizing the dose for treatment.
What They Did:
Researchers enrolled 154 patients with advanced ccRCC who had received 1-3 prior systemic therapies. Participants were randomly assigned to receive either 120 mg or 200 mg of Belzutifan once daily. The study measured the objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety to compare the two dosing regimens.
What They Found:
The study found no significant difference in ORR between the two doses. Additionally, there were no notable differences in DOR, PFS, or OS between the dosing groups. Safety profiles were similar, but the 200 mg group experienced more dose modifications and treatment discontinuations due to side effects, including anemia (low red blood cell count) and hypoxia (low oxygen levels), which were consistent with the known side effects of Belzutifan.
What This Means for You:
For patients with VHL-related kidney cancer, these findings suggest that the standard 120 mg dose of Belzutifan is sufficient and does not need to be increased to achieve better outcomes. This supports the use of the lower dose to minimize side effects while still effectively managing tumor growth.
Full Citation: Agarwal, N., Brugarolas, J., Ghatalia, P., George, S., Haanen, J. B., Gurney, H., Ravilla, R., Van der Veldt, A., Beuselinck, B., Pokataev, I., Suelmann, B. B. M., Tuthill, M. H., Vaena, D., Zagouri, F., Wu, J., Perini, R. F., Liu, Y., Merchan, J., & Atkins, M. B. (2024). Randomized phase 2 dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Annals of Oncology. Link to study.
Participating Institutions: Huntsman Cancer Institute, University of Utah; Simmons Comprehensive Cancer Center, University of Texas Southwestern; Fox Chase Cancer Center; Roswell Park Cancer Institute; Netherlands Cancer Institute; Macquarie University; New York Oncology Hematology; Erasmus Medical Center; Universitair Ziekenhuis Leuven; Moscow City Clinical Oncology Hospital No. 1; Universitair Medisch Centrum Utrecht; Oxford University Hospitals; West Cancer Center & Research Institute; Alexandra General Hospital, Athens; Merck & Co., Inc.; Sylvester Comprehensive Cancer Center, University of Miami; Lombardi Comprehensive Cancer Center, Georgetown University
Belzutifan’s Promise in Treating Eye Tumors
The LITESPARK-004 study investigated the effectiveness of Belzutifan, a HIF-2α inhibitor, in treating retinal hemangioblastomas associated with VHL disease. Retinal hemangioblastomas are common in VHL patients and can lead to vision loss due to exudation (fluid accumulation), hemorrhage (bleeding), and retinal detachment. This study focused on evaluating Belzutifan’s potential to manage these eye tumors non-invasively.
What They Did:
The study included 61 participants, out of which 12 had active retinal hemangioblastomas in 16 eyes. These participants received Belzutifan at a dose of 120 mg daily, and their responses were assessed through regular imaging over a period of around 3 years. The main outcomes measured were the tumor response (improved, stable, or progressed).
What They Found:
The results were highly encouraging, with a 100% response rate in all 16 eyes; every hemangioblastoma showed improvement, with no new tumors or disease progression reported. In the subgroup analysis of larger tumors (measuring 500 microns or more), there was a significant reduction in tumor size by at least 15% within 1 year and by 30% or more by 2 years. The treatment was well-tolerated overall, with common side effects including anemia (low red blood cell count) and fatigue (tiredness).
What This Means for You:
For patients with VHL-related eye tumors, Belzutifan may offer a promising non-surgical option that can effectively reduce tumor size and manage disease progression over the long term. This could mean less reliance on invasive procedures and a greater potential for preserving vision.
Full Citation: Wiley, H. E., Srinivasan, R., Maranchie, J. K., Chhablani, J., Iversen, A. B. B., Kruse, A., Jonasch, E., Gombos, D. S., Else, T., Demirci, H., Maughan, B. L., Hartnett, M. E., Coleman, H. R., Fu, W., Perini, R. F., Liu, Y., Linehan, W. M., Chew, E. Y. (2024). Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study. Ophthalmology. Link to study.
Participating Institutions: National Eye Institute, National Institutes of Health (NIH); National Cancer Institute, NIH; University of Pittsburgh; Aarhus University Hospital; Aalborg University Hospital; University of Texas MD Anderson Cancer Center; University of Michigan; Huntsman Cancer Institute, University of Utah; Byers Eye Institute, Stanford University; VOIANT (Independent Reading Center); Columbia University; Merck & Co., Inc.
Understanding Belzutifan Resistance
This study investigated how specific genetic variations in the HIF-2α protein impact the effectiveness of Belzutifan, a drug used to manage VHL-associated cancers. The research focused on two key alterations: the G323E mutation and phosphorylation at T324, both of which occur near the drug-binding site of HIF-2α. The goal was to understand how these changes affect Belzutifan’s ability to bind to HIF-2α and inhibit its activity.
What They Did:
Researchers used molecular dynamics simulations to model the interactions between Belzutifan and the HIF-2α protein with either the G323E mutation or phosphorylation at T324. These simulations allowed them to observe how these alterations impact the drug’s binding affinity and the overall stability of the HIF-2α complex, which plays a central role in promoting cancer cell survival and growth under low oxygen conditions.
What They Found:
The study found that both the G323E mutation and T324 phosphorylation increase the structural flexibility of the drug-binding site, changing how Belzutifan binds to HIF-2α. The G323E mutation specifically disrupted Belzutifan’s interaction with the HIF-2α binding site, while T324 phosphorylation increased the stability of HIF-2’s interaction with another protein called aryl hydrocarbon receptor nuclear translocator (ARNT). These changes suggest that such genetic variations can lead to resistance against Belzutifan, making the drug less effective for some patients.
What This Means for You:
For patients with VHL disease, understanding how genetic differences impact the effectiveness of treatments like Belzutifan is crucial. If you have a variant like G323E or a similar modification, it may influence how well Belzutifan works for you.
Full Citation: Natarajan, V., Satalkar, V., Gumbart, J. C., & Torres, M. (2024). Molecular Dynamics Reveals Altered Interactions between Belzutifan and HIF-2 with Natural Variant G323E or Proximal Phosphorylation at T324. ACS Omega, 9(36), 37843-37855. Link to study.
Participating Institutions: Georgia Institute of Technology
Combining Belzutifan with Other Treatments
This study discussed innovative approaches for using Belzutifan in treating metastatic renal cell carcinoma (mRCC). It explored how combining Belzutifan with other therapies might overcome resistance mechanisms and improve treatment outcomes for patients with advanced RCC.
What They Did:
The researchers examined clinical data on Belzutifan’s use in mRCC and explored potential resistance mechanisms that limit its effectiveness. They focused on how Belzutifan can be combined with other therapies to enhance its therapeutic effect. The study reviewed ongoing clinical trials and preclinical data to identify the most promising combination strategies.
What They Found:
The study found that resistance to Belzutifan often involves mutations in HIF-2α protein that alter the drug’s binding site, as well as activation of alternative survival pathways in cancer cells. To address these challenges, combinations of Belzutifan with immune checkpoint inhibitors like pembrolizumab and nivolumab, TKIs such as cabozantinib and lenvatinib, and cell cycle checkpoint inhibitors like palbociclib and abemaciclib, were identified as promising approaches. These combinations target multiple pathways simultaneously, potentially overcoming resistance and providing more effective control of tumor growth.
What This Means for You:
For patients with advanced RCC, the combination of Belzutifan with other targeted therapies could offer a more powerful treatment approach, especially in cases where the cancer has become resistant to Belzutifan alone. These new strategies are being tested in clinical trials and could soon provide more comprehensive options for managing metastatic RCC.
Full Citation: Nguyen, C.B., Oh, E., Bahar, P., Vaishampayan, U.N., Else, T., & Alva, A.S. (2024). Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma. Cancers, 16(601). Link to study.
Participating Institutions: Rogel Comprehensive Cancer Center, University of Michigan; University of Michigan Medical School
How Belzutifan is Changing the Game
At the VHL Alliance, we are excited about the potential of Belzutifan to transform how we manage VHL disease. Each of these studies represents a significant step forward, offering new hope for effective, less invasive treatment options that can help you maintain a better quality of life. We encourage you to discuss these findings with your healthcare provider to see if Belzutifan might be right for you.
As always, the VHL Alliance is here to support you on your journey. We will continue to share the latest research and treatment options to help you and your loved ones navigate VHL disease with hope and confidence.