Belzutifan Monotherapy Shows Manageable Safety Profile in Renal Cell Carcinoma: Pooled Analysis
Key Insights
A pooled analysis of four clinical trials (n=576) evaluated the safety of belzutifan monotherapy in patients with renal cell carcinoma (search) (RCC (search)).
Treatment-related adverse events (AEs) occurred in 91.3% of patients, with grade 3-5 AEs reported in 37.7%; however, only 6.4% discontinued treatment due to AEs.
Anemia (84.2%) and hypoxia (16.3%) were the most frequent AEs, generally managed with dose modifications, erythropoiesis-stimulating agents, blood transfusions, or supplemental oxygen.
Belzutifan, a first-in-class hypoxia-inducible factor-2α (HIF-2α (search)) inhibitor, demonstrates a generally manageable safety profile in patients with renal cell carcinoma (search) (RCC (search)), according to a pooled analysis of four clinical trials presented at the 2024 Society of Urologic Oncology (SUO) annual meeting. The analysis, which included 576 patients, showed that while treatment-related adverse events (AEs) were common, few patients discontinued treatment due to these events.
The post hoc pooled analysis included data from the LITESPARK-001, LITESPARK-004, LITESPARK-005, and LITESPARK-013 studies. All patients received belzutifan 120 mg QD and had advanced clear cell RCC (search) with or without von Hippel-Lindau (VHL) disease. The primary focus of the analysis was to characterize the safety profile of belzutifan in this patient population.
Adverse Events and Management
Across the four trials, 91.3% of patients (526) experienced treatment-related AEs, with 37.7% reporting grade 3-5 AEs. However, only 6.4% (37 cases) discontinued treatment due to AEs, and 3.3% (19 cases) resulted in death. Anemia and hypoxia were the most frequently reported AEs, affecting 84.2% and 16.3% of patients, respectively. Other common AEs included fatigue (42.7%) and nausea (24.1%).
The median time to first onset of AEs was within the first three months of treatment: 29 days for anemia, 31 days for hypoxia, and 42 days for fatigue. Management of anemia included erythropoiesis-stimulating agents (ESA) only (22.9%), blood transfusions only (17.5%), or both (12.8%). The median time to onset of ESA use was 85 days, with a median of five injections per patient. The median time to the first blood transfusion was 87 days, with a median of two transfusions per patient.
For patients experiencing hypoxia, 70.2% were treated with supplemental oxygen. The median time to onset of supplemental oxygen therapy was 43 days, with a median duration of 9 days. The median time to resolution of hypoxia was 11 days.
Clinical Implications
This pooled analysis represents the largest safety dataset to date for patients receiving a HIF-2α (search) inhibitor for RCC (search). The findings suggest that belzutifan has a manageable safety profile, particularly when AEs are promptly addressed with appropriate interventions. Belzutifan is already approved in the United States and Canada for VHL disease (search)-associated neoplasms and, in the US, for adult patients with advanced RCC previously treated with a PD-(L)1 inhibitor and a VEGF-TKI. Its unique mechanism of action offers a valuable treatment option, especially for patients with VHL disease-associated tumors, where it remains the only approved therapy.