Novel Approaches to Targeting Cancers Associated with VHL Mutations

Division Of Basic Sciences - Nci

Investigators

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Abstract

Understanding the consequences of VHL inactivation has informed the rational preclinical and clinical development of therapies in patients with VHL deficient (clear cell) renal cancer. Aberrant overexpression of the transcriptionally active hypoxia inducible factors, particularly upregulation of HIF2, is an important step in the development of clear cell kidney cancer. Initial therapeutic advances were based on targeting downstream consequences of HIF upregulation. While effective in inducing tumor regression in patients with sporadic forms of clear cell kidney cancer, the clinical utility of these agents (such as sunitinib, pazopanib and vandetanib) in patients with inherited, VHL-disease associated manifestations was limited, both due to modest activity and intolerable side effects. Furthermore, resistance, both primary and secondary, is common and most patient with advanced clear cell RCC die from their disease. While immune checkpoint inhibitors targeting the PD1/PDL1 and/or CTLA4 axes have activity in patients with sporadic clear cell RCC, including the induction of long-term remissions in some patients, their utility in VHL disease remains unproven. We hypothesized that directly targeting HIF2 might be associated with activity in VHL disease associated tumors and that this approach would be safe and well tolerated. I lead an ongoing phase 2 study of the novel HIF 2 inhibitor, belzutifan,in patients with localized renal tumors associated with VHL disease, in collaboration with academic centers in the US and Europe and industry collaborators. The initial publication detailing the results from this study (New England Journal of Medicine, 2021) highlighted the activity of this agent with response rates approaching 50% in renal tumors associated with VHL; activity was also seen in pancreatic neuroendocrine tumors, CNS and retinal hemangioblastomas. The agent also had an acceptable toxicity profile, with the majority of the patients able to remain on study treatment for 2 or more years. Additionally, the incidence of surgical intervention during this period was very low. By studying the natural evolution of VHL disease in patients seen at the NCI in the absence of systemic intervention over a period of 16 years, we showed that approximately 75% of patients needed at least one renal surgical intervention and over 40% developed chronic kidney disease (European Urology, 2025). These data served as external comparator and further highlighted the potential clinical utility of belzutifan in this patient population. Belzutifan was approved by the FDA in 2021 for the treatment of some patients with VHL-associated tumors. Long term follow up from this study is essential to help us understand the durability of responses, emergence and incidence of resistance, and long term toxicity/tolerability. Results from the study with a median follow up of 4 years were analyzed and published this year (Lancet Oncology, 2025). Additional follow up data (median follow up of 5 years) was also presented at the 2025 annual ASCO meeting. The most recent data continue to show a high response rate (ORR 70% in RCC, 50% in CNS hemangioblastomas, and 90% in pancreatic neuroendocrine tumors). Responses are durable (median duration of response and median PFS not reached for RCC), and there were no new adverse events of concern. 19/61 patients required at least one surgical intervention, suggesting the emergence of resistance in some patients. Patients continue to be followed on study and additional long term follow up data will be forthcoming. Understanding the basis of resistance to HIF2 inhibitors and developing treatment strategies that improve upon the activity of single agent belzutifan are important areas of study in my group. An ongoing collaboration with investigators from Dana Farber Cancer Center/Harvard (Developing a Translation Pipeline for VHL Mutant Malignancies- UO1 grant-1U01CA236489-01) will focus on addressing these issues. One approach that is currently being evaluated in the clinic is the use of the cdk 4/6 inhibitor palbociclib, in combination with the PD1 inhibitor, sasanlimab, in a phase 1/2 study of patients with advanced treatment refractory clear cell RCC. This study is based on findings that suggest the inhibition of cdk4/6 is synthetic lethal in patients with VHL-deficient kidney cancer. Other combination approaches in patients with VHL disease associated tumors are currently under development.