Belzutifan in Previously Treated Advanced Renal Cell Carcinoma

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On December 14, 2023, the hypoxia-inducible factor inhibitor belzutifan (Welireg) was approved for patients with unresectable locally advanced or metastatic clear cell renal cell carcinoma with disease progression on previous treatment with a PD-1 or PD-L1 inhibitor and a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor.1


Belzutifan has a boxed warning for embryofetal toxicity. It also has warnings/precautions for anemia and hypoxia.

Supporting Efficacy Data

Approval was based on the open-label LITESPARK-005 trial ( identifier NCT04195750), in which 746 patients were randomly assigned to belzutifan at 120 mg once daily (n = 374) or everolimus at 10 mg once daily (n = 372).

The trial met its co-primary endpoint of progression-free survival. At 18 months, 22.5% of patients receiving belzutifan remained progression-free, compared to 9% of patients receiving everolimus. The hazard ratio for progression-free survival on blinded independent central review favored the belzutifan group (0.75, 95% confidence interval [CI] = 0.63–0.90, P = .0008). Kaplan-Meier curves showed nonproportional hazards, with curves separating in favor of belzutifan at approximately 6 months. Median progression-free survival was similar in the two groups at 5.6 months (95% CI = 3.9–7.0 months) in the belzutifan group vs 5.6 months (95% CI = 4.8–5.8 months) in the everolimus group. Overall survival data were immature at the time of analysis. An objective response occurred in 22% vs 4% of patients, with a complete response in 3% vs 0%.

How It Is Used

The recommended dose is 120 mg once daily until disease progression or unacceptable toxicity. Product labeling provides instructions on dosage modification for adverse reactions including anemia, hypoxia, and grade 3 or 4 adverse reactions. For concomitant use of UGT2B17 inhibitors (diclofenac, ibuprofen) or CYP2C19 inhibitors (omeprazole, ticlopidine), signs or symptoms of anemia and hypoxia should be monitored and the dose of belzutifan reduced.

Safety Profile

Among 732 patients in the safety population of LITESPARK-005, the most common grade 3 adverse events included hypoxia (10% vs 1.4%) and fatigue (3.3% vs 6%). The most common grade 3 or 4 laboratory abnormalities in the belzutifan group were decreased hemoglobin (29%) and lymphocytes (8%) and increased creatinine (4.7%). Serious adverse events occurred in 38% of the belzutifan group, most commonly hypoxia (7%), anemia (5%), pneumonia (3.5%), and hemorrhage (3%).

Belzutifan has a boxed warning for embryofetal toxicity. It also has warnings/precautions for anemia and hypoxia. Patients should be advised not to breastfeed while receiving belzutifan. 


1. Welireg (belzutifan) tablets, prescribing information, Merck & Co, Inc, December 2023. Available at Accessed January 2, 2024.