Renal cell and non-renal cell carcinomas associated with von Hippel−Lindau (VHL) disease show evidence of response to the hypoxia-inducible factor inhibitor belzutifan, reports a study in The New England Journal of Medicine.
The phase 2, open-label trial included 61 adults with VHL disease, with diagnosis based on the presence of germ- line VHL alterations and at least one renal cell carcinoma measuring at least 10 mm. All patients were treated with belzutifan, a novel oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, at a dose of 120 mg/day. Complete or partial objective responses were assessed by an independent radiology review committee, following standard criteria. Responses of non-renal cell cancers, which included pancreatic lesions in all patients, were also analyzed, along with safety outcomes.
The patients were 32 men and 29 women, median age 41 years. All but 2 had undergone previous surgery or ablative procedures, with a median of 4 procedures per patient. Median follow-up was 21.8 months.
The objective response rate in patients with renal cell carcinoma was 49%. All of these were partial responses; another 49% of patients had a best response of stable disease. Among evaluable patients with partial responses, the median linear growth rate was 4.1 mm per year before belzutifan versus −5.6 mm per year on treatment. Responses were also observed for non-renal cancers: 47 of 61 for pancreatic cancers (77%) and 15 of 50 for central nervous system hemangioblastomas (30%).
Adverse events included anemia in 90% of patients and fatigue in 66%. Treatment was discontinued in 7 patients, voluntarily in 4 of them.
Patients with VHL disease are at high risk of renal cell carcinoma as a result of VHL gene inactivation and constitutive activation of HIF-2α. Some effective form of systemic therapy could be of benefit by controlling tumor growth and reducing the burden of surgery.
The study demonstrates activity of HIF-2α inhibition with belzutifan against renal cell and non-renal cell carcinomas associated with VHL disease. Side effects are common but generally low grade. Although acknowledging the study's limitations, the authors point out that randomized trials are unlikely due to the lack of other non-surgical treatments for VHL disease [Jonasch E, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N Engl J Med 2021; 385:2036–2046. doi: 10.1056/NEJMoa2103425].