Belzutifan

The open-label phase III LITESPARK-005 trial (NCT04195750) compared belzutifan with everolimus in patients with advanced clear cell renal cell carcinoma who experienced disease progression after one to three lines of prior systemic therapies, including immune checkpoint inhibitors and VEGF-targeted treatments. The co-primary end points of the study were PFS, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 via blinded independent central review, and OS.[25]The FDA approved belzutifan for the treatment of advanced renal cell carcinoma in the second-line and beyond based on the PFS benefit observed in the trial. However, the trial did not meet the co-primary end point of OS. Also, the cost of belzutifan is $31,000 per month for uninsured patients, while everolimus, a generic drug, costs approximately $450 per month (in 2024 dollars).

The open-label phase III LITESPARK-005 trial (NCT04195750) compared belzutifan with everolimus in patients with advanced clear cell renal cell carcinoma who experienced disease progression after one to three lines of prior systemic therapies, including immune checkpoint inhibitors and VEGF-targeted treatments. The co-primary end points of the study were PFS, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 via blinded independent central review, and OS.[25]The FDA approved belzutifan for the treatment of advanced renal cell carcinoma in the second-line and beyond based on the PFS benefit observed in the trial. However, the trial did not meet the co-primary end point of OS. Also, the cost of belzutifan is $31,000 per month for uninsured patients, while everolimus, a generic drug, costs approximately $450 per month (in 2024 dollars).

The trial demonstrated a significant improvement in PFS with belzutifan compared with everolimus (HR, 0.75; 95% CI, 0.63–0.90; P = .0016). Objective response rates were also 19.2% higher in the belzutifan arm (95% CI, 14.8%–24.0%). However, OS did not improve significantly (HR, 0.88; 95% CI, 0.73–1.07; P = .20), indicating no clinically meaningful survival difference. The lack of OS benefit raises concerns about the clinical meaningfulness of the PFS improvement.[25][Level of evidence B1]

The open-label phase III LITESPARK-005 trial (NCT04195750) compared belzutifan with everolimus in patients with advanced clear cell renal cell carcinoma who experienced disease progression after one to three lines of prior systemic therapies, including immune checkpoint inhibitors and VEGF-targeted treatments. The co-primary end points of the study were PFS, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 via blinded independent central review, and OS.[25]The FDA approved belzutifan for the treatment of advanced renal cell carcinoma in the second-line and beyond based on the PFS benefit observed in the trial. However, the trial did not meet the co-primary end point of OS. Also, the cost of belzutifan is $31,000 per month for uninsured patients, while everolimus, a generic drug, costs approximately $450 per month (in 2024 dollars).

Grade 3 or higher adverse events of any cause occurred in 61.8% of patients in the belzutifan group (grade 5 severity occurred in 3.5% of patients) and in 62.5% of patients in the everolimus group (grade 5 severity occurred in 5.3% of patients). Adverse events led to treatment discontinuation in 5.9% of patients in the belzutifan group and 14.7% of patients in the everolimus group.