Belzutifan Improves Response in Advanced Clear-Cell RCC

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For patients with advanced clear-cell renal-cell carcinoma (RCC), the hypoxia-inducible factor 2α inhibitor belzutifan improves outcomes compared with everolimus, reports a randomized trial in The New England Journal of Medicine.

The phase 3, open-label LITESPARK-005 trial enrolled 746 patients with advanced clear-cell RCC at 147 study sites. All patients had received first-line treatment with immune checkpoint inhibitors and antiangiogenic drugs. Patients were randomly assigned to once-daily treatment with belzutifan (120 mg) or the mammalian target of rapamycin inhibitor, everolimus (10 mg). Progression-free and overall survival were evaluated as coprimary outcomes.

On interim analysis after a median of 18.4 months, progression-free survival was 24.0% for patients assigned to belzutifan versus 8.3% in the everolimus group. Belzutifan also produced a higher objective response rate: 21.9% versus 3.5%. At a second interim analysis, the median overall survival was 21.4 months with belzutifan and 18.1 months with everolimus. Eighteen-month survival was 55.2% and 50.6%, respectively; the difference was nonsignificant.

In both groups, more than 60% of patients experienced grade 3 or higher adverse events. Rates of treatment discontinuation due to adverse events were 5.9% with belzutifan and 14.7% with everolimus. Belzutifan was associated with a longer time to worsening of RCC-specific symptoms and to a decline in health-related quality of life.

In early-phase trials, belzutifan showed clinical activity against clear-cell RCC. The LITESPARK-005 results demonstrate improvements in progression-free survival and an objective response rate with belzutifan in patients who were heavily pretreated with advanced clear-cell RCC compared with everolimus. The authors discuss the clinical implications of their findings; studies comparing belzutifan combinations with other RCC therapies are ongoing [Choueiri TK, et al.; LITESPARK-005 Investigators. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med 2024; 391:710–721. doi: 10.1056/NEJMoa2313906].

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