Systemic Therapy Options in VHL Disease

Systemic therapy for von Hippel-Lindau (VHL) disease has been evolving over the past decade in conjunction with our understanding of the molecular biology of VHL deficiency. Treatments have been developed that modulate some of the downstream consequences of VHL loss, including vascular endothelial growth factor receptor (VEGFR) inhibitors. Clinical trials of VEGFR inhibitors in VHL disease demonstrate clinical benefit, but class-specific toxicities render these agents impractical for many patients. Hypoxia-inducible factor 2 alpha (HIF2a) inhibitors have recently emerged and demonstrate efficacy and tolerability, and induce response in multiple organ manifestations in patients with VHL disease. Ongoing work to refunctionalize or replace mutated VHL may provide another avenue to improve the outcome of patients with VHL disease.