Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma.
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Choueiri Toni K, Powles Thomas, Peltola Katriina, de Velasco Guillermo, Burotto Mauricio, Suarez Cristina, Ghatalia Pooja, Iacovelli Roberto, Lam Elaine T, Verzoni Elena, Gümüş Mahmut, Stadler Walter M, Kollmannsberger Christian, Melichar Bohuslav, Venugopal Balaji, Gross-Goupil Marine, Poprach Alexandr, De Santis Maria, Schutz Fabio A, Park Se Hoon, Nosov Dmitry A, Porta Camillo, Lee Jae Lyun, Garcia-Del-Muro Xavier, Biscaldi Elisa, Manneh Kopp Ray, Oya Mototsugu, He Li, Wang Aobo, Perini Rodolfo F, Vickery Donna, Albiges Laurence, Rini Brian, LITESPARK-005 Investigators
Аннотация
METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response).
RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively.
CONCLUSIONS: 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. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).