Recent advances in first-line therapy for clear-cell renal-cell carcinoma (ccRCC), including immune checkpoint and antiangiogenic agents, have led to knowledge gaps in selecting subsequent therapy for patients with disease progression. Over 90% of ccRCC exhibit VHL gene mutations, deletions, or methylation, resulting in pathological HIF-2α accumulation. Therefore, there is a need for medications with new therapeutic mechanisms for these patients.
The Mechanism of Belzutifan
Belzutifan is an orally active and selective HIF-2α inhibitor with an IC50 of 9 nM. As a second-generation HIF-2α inhibitor, this molecule significantly increases potency and improves pharmacokinetic profile. Belzutifan is a potential treatment for ccRCC.
Belzutifan: A HIF-2α Inhibitor for Renal-Cell Carcinoma Research
The Phase III multicenter LITESPARK-005 study adopted an open-label, randomized design to compare Belzutifan with everolimus as active control. It involved 746 adults with stage IV ccRCC. These patients’ disease had progressed after treatment with a PD-1 or PD-L1 inhibitor and a VEGFR-TKI. Participants were given belzutifan (120 mg) or everolimus (10 mg) orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary endpoints were progression-free survival and overall survival.
At the first interim analysis (median follow-up: 18.4 months), both groups had a median PFS of 5.6 months. However, the 18-month PFS rate was significantly higher with belzutifan (24.0% vs. 8.3%, two-sided P=0.002). Confirmed responses occurred in 21.9% of belzutifan-treated patients versus 3.5% with everolimus (P<0.001). Complete responses were observed only in the belzutifan group (2.7–3.5%). At the second interim analysis (median follow-up: 25.7 months), median OS was 21.4 months with belzutifan and 18.1 months with everolimus. However, the difference did not meet statistical significance (HR=0.88; 95% CI: 0.73–1.07; P=0.20).
Belzutifan showed a significant benefit over everolimus in progression-free survival and objective response. And it didn’t bring new safety signals.
In summary, belzutifan is a novel HIF-2α inhibitor. It has shown significant benefit over everolimus in progression-free survival and objective response for advanced ccRCC patients who progressed after immune checkpoint and antiangiogenic therapies.
References
[1]. Xu R, et al. J Med Chem. 2019 Aug 8;62(15):6876-6893.
[2]. Choueiri, Toni K et al. N Engl J Med. 2024 Aug 22;391(8):710-721.
