KEY TAKEAWAYS
- The MK-6482-005 phase III trial aimed to compare belzutifan to everolimus for advanced ccRCC patients previously treated with other therapies.
- The primary endpoints were PFS and OS. Secondary endpoints were ORR, safety, TTD, PFS, and ORR.
- The result demonstrated that belzutifan outperformed everolimus in PFS and ORR for advanced ccRCC post-ICIs/anti-angiogenics, with a safe profile consistent with prior studies.
Belzutifan, a first-in-class oral HIF-2α inhibitor, is approved in the US for several cancers and shows promise for advanced clear cell renal cell carcinoma (ccRCC).
Patients aged 18 years or older, with Karnofsky Performance Status (KPS) of 70% or higher and advanced ccRCC having received 1-3 prior systemic regimens, including anti–PD-(L)1 monoclonal antibody and VEGF-TKI, were randomly assigned in a 1:1 ratio to receive either belzutifan 120 mg once daily or everolimus 10 mg once daily until disease progression or unacceptable toxicity.
The primary endpoints were progression-free survival (PFS) based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 assessed by blinded independent central review (BICR) and overall survival (OS). Key secondary endpoints involved objective response rate (ORR) based on RECIST 1.1 by BICR, safety, and time to deterioration (TTD) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS). PFS and ORR were formally tested at the first interim analysis (IA1).
About 374 patients received belzutifan, and 372 received everolimus. At the first analysis (median fu 18.4 mo; range 9.4–31.7), belzutifan demonstrated superior PFS and ORR compared to everolimus. OS did not reach statistical significance. These findings were consistent in the second analysis (median fu 25.7 mo; range 16.8–39.1).
Complete responses were observed in 13 patients (3.5%) with belzutifan and none with everolimus. More patients remained progression-free with belzutifan at 12 months (PFS rate 33.7% vs. 17.6%) and 18 months (22.5% vs. 9.0%). Ongoing treatment was reported in 22.6% vs. 5.0% of patients, while study therapy discontinuation due to adverse events(AEs) occurred in 5.9% vs. 14.7%.
Grade 3-5 treatment-related adverse events(TRAEs) were comparable at 38.7% vs. 39.4%. TTD for FKSI-DRS favored belzutifan (median not reached vs 12.0 mo; HR 0.53; 95% CI 0.41–0.69; nominal P<.0001).
The result demonstrated that belzutifan outperformed everolimus in PFS and ORR for advanced ccRCC post-ICIs/anti-angiogenics, with a safe profile consistent with prior studies.
Clinical Trial: https://www.clinicaltrials.gov/study/NCT04195750
Albiges L, Rini BI, Peltola K, De Velasco Oria GA, Burotto M, Suarez Rodriguez C, Ghatalia P, Iacovelli R, Lam ET, Verzoni E, Gumus M, Stadler WM, Kollmannsberger CK, Melichar B, Venugopal B, Wang A, Perini R, Vickery D, Powles TB, Choueiri TK. Belzutifan versus everolimus in participants with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Ann Oncol. 2023;34(suppl_2):S1254-S1335. doi:10.1016/annonc/annonc1358.
