Transcription factors were initially considered undruggable with small molecules, but the identification of a suitable drug-binding pocket in hypoxia-inducible factor 2α (HIF-2α) opened the door for the rational design of belzutifan as a HIF-2α inhibitor. The LITESPARK-005 study established this novel mechanism of action in advanced clear cell renal cell carcinoma (RCC) and introduced phase III, randomised evidence of the successful therapeutic targeting of a transcription factor in cancer.
Belzutifan has shown a significant benefit over everolimus with respect to progression-free survival (PFS) in patients with advanced clear cell RCC who had disease progression after receiving immune checkpoint inhibitor (ICI) and antiangiogenic therapies. A significant difference between the two groups with respect to the occurrence of an objective response was also observed. The findings are reported by Dr. Toni K. Choueiri of the Dana–Farber Cancer Institute in Boston, MA, US, and colleagues on 21 August 2024 in The New England Journal of Medicine.
Mutations, deletions, or methylation of the VHL gene occur in more than 90% of clear cell RCC and result in dysregulation of the HIF pathway through accumulation of HIF-2α, which leads to tumourigenesis, angiogenesis, and metastasis. HIF-2α is a transcription factor that upregulates the expression of hundreds of genes which play a known or potential role in the growth and progression of clear cell RCC, the authors wrote in the background.
Belzutifan is a potent small molecule inhibitor of HIF-2α that prevents heterodimerisation with HIF-1β into an active transcription factor and has shown activity in clear cell RCC. The phase III, open-label, randomised LITESPARK-005 study compared the efficacy and safety of belzutifan with everolimus in pantients with advanced clear cell RCC who had disease progression after receiving ICI and antiangiogenic therapies.
Patients were randomly assigned in a 1:1 ratio to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable side effects occurred. The dual primary endpoints were PFS and overall survival (OS). The key secondary endpoint was the occurrence of an objective response, defined as a confirmed complete or partial response.
A total of 374 patients were assigned to belzutifan and 372 to everolimus. At the first interim analysis with a median follow-up of 18.4 months, the median PFS was 5.6 months in both groups. At 18 months, 24.0% of patients in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided p = 0.002, which met the prespecified significance criterion).
A confirmed objective response occurred in 21.9% of patients (95% confidence interval [CI] 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI 1.9 to 5.9) in the everolimus group (p < 0.001, which met the prespecified significance criterion). As of the last data cut-off date, more patients in the belzutifan group than in the everolimus group were receiving ongoing treatment, and the median duration of treatment with belzutifan was nearly double that of everolimus.
At the second interim analysis with a median follow-up of 25.7 months, the median OS was 21.4 months in the belzutifan group and 18.1 months in the everolimus group. At 18 months, 55.2% and 50.6% of patients, respectively, were alive (hazard ratio for death 0.88, 95% CI 0.73 to 1.07; two-sided p = 0.20, which did not meet the prespecified significance criterion).
Treatment with belzutifan was associated with no new safety signals. Grade 3 or higher adverse events of any cause occurred in 61.8% of patients in the belzutifan group with grade 5 occurring in 3.5% and in 62.5% in the everolimus group with grade 5 occurring in 5.3%. Adverse events led to discontinuation of treatment in 5.9% and 14.7% of patients, respectively.
Anaemia and hypoxia were generally well managed with an erythropoietin stimulating agent and oxygen therapy in accordance with the study protocol specifications. The authors commented that belzutifan has a safety profile distinct from other available late line therapies for clear cell RCC. Attention to the management of adverse events such as anaemia and hypoxia will be required as belzutifan is incorporated into clinical practice.
Patients who received belzutifan had a longer time to confirmed worsening of disease-specific symptoms and deterioration in health-related quality-of-life than patients who received everolimus, which provides further support for the use of belzutifan in patients with advanced clear cell RCC.
The difference in OS did not reach significance in this heavily pretreated population with advanced disease. Results of the final protocol-specified analysis are pending. The authors commented that the LITESPARK-005 study enrolled a population with more heavily pretreated disease which reflects the context in which everolimus is currently administered. Studies investigating belzutifan combinations as compared with other therapies are ongoing.
The study was funded by Merck Sharp and Dohme, a subsidiary of Merck.
Reference
Choueiri TK, Powles T, Peltola K, et al. For the LITESPARK-005 Investigators. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Engl J Med 2024;391:710-721.