As reported in The New England Journal of Medicine by Choueiri and colleagues, the phase III LITESPARK-005 trial has shown improved progression-free survival with the hypoxia-inducible factor–2α inhibitor belzutifan vs everolimus in previously treated patients with advanced clear-cell renal cell carcinoma.
Study Details
In the open-label trial, 746 patients from sites in 6 regions who had received immune checkpoint inhibitor (ICI) therapy and antiangiogenic therapy were randomly assigned between March 2020 and January 2022 to receive belzutifan at 120 mg (n = 374) or everolimus at 10 mg (n =372) once daily until progression or unacceptable toxicity. The primary endpoints were progression-free survival and overall survival.
Treatment Outcomes
At first interim analysis at median follow-up of 18.4 months, median progression-free survival was 5.6 months (95% confidence interval [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; rates at 18 months were 24.0% vs 8.3%, respectively (P = .002, meeting the prespecified significance criterion). Rates at 6 months were 46.6% vs 42.5% and rates at 12 months were 33.4% vs 17.1%, respectively.
A total of 47.3% of the belzutifan group and 64.5% of the everolimus group received subsequent anticancer therapy. At second interim analysis of overall survival at a median follow-up of 25.7 months, median overall survival was 21.4 months (95% CI = 18.2–24.3 months) in the belzutifan group vs 18.1 months (95% CI = 15.8–21.8 months) in the everolimus group; rates at 18 months were 55.2% vs 50.6% (HR = 0.88, 95% CI = 0.73-1.07, P = .20, not meeting the prespecified significance criterion).
Objective response was observed in 21.9% (95% CI = 17.8%–26.5%) of the belzutifan group vs 3.5% (95% CI = 1.9%-5.9%) of the everolimus group (P < .001).
Adverse Events
Grade ≥ 3 adverse events occurred in 61.8% of the belzutifan group vs 62.5% of the everolimus group; the most common were anemia (32.5%) and hypoxia (10.5%) in the belzutifan group and anemia (18.1%) and hyperglycemia (5.6%) in the everolimus group. Serious adverse events occurred in 42.2% vs 38.1% of patients. Adverse events led to discontinuation of treatment in 5.9% vs 14.7%. Grade 5 adverse events occurred in 13 patients (3.5%) in the belzutifan group and 19 patients (5.3%) in the everolimus group; death was considered related to treatment in 1 patient (0.3%) in the belzutifan group (due to multiple organ dysfunction syndrome) and 2 patients (0.6%) in the everolimus group (due to sepsis and acute kidney injury).
The investigators 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. Belzutifan was associated with no new safety signals.”
Disclosure: The study was funded by Merck Sharp and Dohme, a subsidiary of Merck.
Toni K. Choueiri, MD, Dana-Farber Cancer Institute, is the corresponding author for The New England Journal of Medicine article.
