Belzutifan Improved Survival, Response Among Patients With Advanced Clear-Cell Renal Cell Carcinoma

According to results from the multicenter, phase 3 LITESPARK-005 trial, belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2α, significantly improved progression-free survival (PFS) and overall response among patients with advanced clear-cell renal cell carcinoma, who had previously been treated with immune checkpoint and antiangiogenic therapies. 

Toni K. Choueiri, MD, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors wrote, “Recent advances in first-line therapy for clear-cell renal cell carcinoma, including immune checkpoint inhibitors and antiangiogenic agents, have led to knowledge gaps in selecting subsequent therapy for patients with disease progression. There is a need for medications with new therapeutic mechanisms for these patients.”

In this open-label, active-controlled trial, 746 patients were randomized on a 1-to-1 basis to receive either 120 mg of belzutifan (n = 374) or 10 mg of everolimus (n = 372), once daily until disease progression or unacceptable toxicity. Dual primary end points were PFS and overall survival (OS). Key secondary end points were objective response and safety. 

At the first interim analysis, with a median follow-up of 18.4 months, the median PFS was 5.6 months in both treatment arms with 24% of patients alive and free of progression in the belzutifan arm and 8.3% of patients alive and free of progression in the everolimus arm (two-sided P = .002). A confirmed objective response occurred in 21.9% of patients in the belzutifan arm and 3.5% of patients in the everolimus arm (P < .001). At the second interim analysis, with a median follow-up of 25.7 months, the median OS was 21.4 months in the belzutifan arm and 18.1 months in the everolimus arm. At 18 months, 55.2% of patients were alive in the belzutifan arm and 50.6% of patients were alive in the everolimus arm (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.73 to 1.02; two-sided P = .20). 

Grade ≥3 adverse events of any cause occurred in 61.8% of patients in the belzutifan arm (3.5% of which were grade 5) and 62.5% of patients in the everolimus arm (5.3% of which were grade 5). Adverse events that led to treatment discontinuation occurred in 5.9% of patients in the belzutifan arm and 14.7% of patients in the everolimus arm. 

As Dr Choueiri et al, concluded, “Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies.” 

Source: 

Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. Published online: August 21, 2024. doi: 10.1056/NEJMoa2313906