Belzutifan Approved for Advanced Renal Cell Carcinoma

Renal cell carcinoma.

The FDA has approved belzutifan (Welireg™, Merck & Co., Inc.) for advanced renal cell carcinoma (RCC) subsequent to a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).  

Why it matters: “Belzutifan is a first-in-class oral hypoxia-inducible factor 2alpha (HIF-2α) inhibitor approved in the US for patients with Von Hippel-Lindau disease–associated RCC, primitive neuroectodermal tumors, and central nervous system hemangioblastoma and has antitumor activity in clear cell RCC,” wrote Laurence Albiges, MD, PhD, Chair of the Genitourinary Oncology Group and Vice Chair of the Department of Cancer Medicine at the Gustave Roussy Institute, in France, and colleagues, in their published results of the LITESPARK-005 trial (NCT04195750), on which approval was based.

What they studied: Efficacy was measured in the phase 3, open-label, head-to-head trial in which 746 patients with unresectable locally advanced or metastatic clear cell RCC that had progressed following both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF-TKI were enrolled. Patients were randomized 1:1 to receive either 120 mg of belzutifan or 10 mg of everolimus once daily. Randomization was stratified according to International Metastatic RCC Database Consortium (IMDC) risk category and number of previously received VEGF-TKIs.

The primary end points studied were progression- free survival, assessed by blinded independent central review, and overall survival.

What they found: Belzutifan produced a statistically significant improvement in progression-free survival compared with everolimus, with a hazard ratio of 0.75 [(95% CI: 0.63, 0.90). Kaplan-Meier curves reflected nonproportional hazards, with a similar median progression-free survival estimate of 5.6 months. Overall survival results were immature at the current analysis, with no trend towards a detriment observed.

Approval was further supported by an improved tolerability for belzutifan compared with everolimus via a descriptive analysis of patient-reported symptom and functional outcomes.

Adverse events: The most common adverse events experienced by ≥25% of patients receiving belzutifan were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase.

Conclusion: “Belzutifan was associated with a statistically significant improvement in progression-free survival and overall response rate versus everolimus for patients with advanced clear cell RCC after immune checkpoint and anti-angiogenic therapies,” concluded Dr. Albiges and colleagues. “The safety profile of belzutifan was consistent with prior reports with no new safety signals.”

Instructions: The recommended dosage of belzutifan is 120 mg orally, once daily, until disease progression or unacceptable toxicity.

For More Information

Albiges L, Rini B, Peltola K, et al (2023). LBA88 Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Ann Oncol [ESMO Congress Abstracts], 34(suppl_2):1329-1330. DOI:10.1016/j.annonc.2023.10.090 (2023). A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). NLM identifier: NCT04195750.

Welireg™ (belzutifan) prescribing information (2023). Merck & Co., Inc. Available at:

US Food and Drug Administration (2023). FDA approves belzutifan for advanced renal cell carcinoma. Available at:

Image credit: Nephron. Licensed under CC BY-SA 3.0

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