On 14 December 2023, the US Food and Drug Administration (FDA) approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following a programmed death receptor 1 (PD1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI).
Efficacy was evaluated in LITESPARK-005 (NCT04195750), an open-label, randomised, head-to-head study of 746 patients with unresectable locally advanced or metastatic clear cell RCC that had progressed following both a PD1 or PD-L1 checkpoint inhibitor and a VEGF TKI. Patients were randomised 1:1 to receive 120 mg belzutifan or 10 mg everolimus once daily. Randomisation was stratified by International Metastatic RCC Database Consortium risk category and number of prior VEGF TKIs.
The major efficacy outcome measures were progression-free survival (PFS) assessed by blinded independent central review and overall survival (OS).
A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus, with a hazard ratio of 0.75 (95% confidence interval [CI] 0.63, 0.90; 1-sided p-value = 0.0008). Kaplan-Meier curves reflected non-proportional hazards with similar median PFS estimates of 5.6 months (95% CI 3.9, 7.0) in the belzutifan arm and 5.6 months (95% CI 4.8, 5.8) for those receiving everolimus. While OS results were immature at the current analysis, with 59% of deaths reported, no trend towards a detriment was observed. A descriptive analysis of patient-reported symptom and functional outcomes was supportive of improved tolerability for belzutifan compared to everolimus.
The most common adverse reactions (≥25% incidence) in patients receiving belzutifan were decreased haemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase.
The recommended belzutifan dose is 120 mg administered orally once daily until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted priority review.
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