- 2024-08-01
- The New England journal of medicine 391(8)
- Toni K Choueiri
- Thomas Powles
- Katriina Peltola
- Guillermo de Velasco
- Mauricio Burotto
- Cristina Suarez
- Pooja Ghatalia
- Roberto Iacovelli
- Elaine T Lam
- Elena Verzoni
- Mahmut Gümüş
- Walter M Stadler
- Christian Kollmannsberger
- Bohuslav Melichar
- Balaji Venugopal
- Marine Gross-Goupil
- Alexandr Poprach
- Maria De Santis
- Fabio A Schutz
- Se Hoon Park
- Dmitry A Nosov
- Camillo Porta
- Jae Lyun Lee
- Xavier Garcia-Del-Muro
- Elisa Biscaldi
- Ray Manneh Kopp
- Mototsugu Oya
- Li He
- Aobo Wang
- Rodolfo F Perini
- Donna Vickery
- Laurence Albiges
- Brian Rini
Study Design
- Type
- Randomized Controlled Trial (RCT)
- Sample size
- n = 374
- Population
- participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies (746 total)
- Methods
- Phase 3, multicenter, open-label, active-controlled trial; participants randomly assigned 1:1 to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects
- Blinding
- Open-label
- Duration
- until disease progression or unacceptable toxic effects (median follow-up 18.4 months at first interim analysis, 25.7 months at second interim analysis)
- Funding
- Industry-funded
- Large Human Trial
- Highly Cited
Background
Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies.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.).