Background
Phase III, open-label RCT. 746 patients with previously treated advanced clear-cell RCC who had received 1–3 prior lines including a PD-1/L1 inhibitor and a VEGF-targeted therapy. Belzutifan (HIF-2α inhibitor) compared to everolimus (mTOR inhibitor, prior standard in this setting). Belzutifan targets HIF-2α, a transcription factor driving VHL-mutated ccRCC.
Interventions and follow up
Arm A: Belzutifan 120mg/day orally
Arm B: Everolimus 10mg/day orally
Primary endpoint: PFS and OS (co-primary)
mFollow up: 25.7 mo
Arm B: Everolimus 10mg/day orally
Primary endpoint: PFS and OS (co-primary)
mFollow up: 25.7 mo
Results
PFS: 5.6 vs 5.6 mo (medians), HR 0.75, P=.002
OS: 21.4 vs 18.1 mo, HR 0.88, P=.24 — not significant
ORR: 22.7% vs 3.5%
Duration of response: 19.3 mo vs 6.0 mo
OS: 21.4 vs 18.1 mo, HR 0.88, P=.24 — not significant
ORR: 22.7% vs 3.5%
Duration of response: 19.3 mo vs 6.0 mo
Adverse events
Overall: Grade ≥3 AEs 61.5% vs 62.6%; discontinuation due to AEs 4.3% vs 7.4%; dose reductions 56.4% vs 49.1%
Hematologic: Anemia grade ≥3 24.1% vs 7.1% (HIF-2α inhibition reduces erythropoietin)
Respiratory/constitutional: Hypoxia (any) 8.6% vs 0.8%; fatigue grade ≥3 6.6% vs 5.6%
Hematologic: Anemia grade ≥3 24.1% vs 7.1% (HIF-2α inhibition reduces erythropoietin)
Respiratory/constitutional: Hypoxia (any) 8.6% vs 0.8%; fatigue grade ≥3 6.6% vs 5.6%
Conclusions
Belzutifan significantly improved PFS versus everolimus in previously treated ccRCC, with a notably higher ORR (22.7% vs 3.5%) and more durable responses. OS did not reach statistical significance. Belzutifan establishes HIF-2α inhibition as a new mechanism of action in the RCC therapeutic armamentarium.
Key Limitations
Key Limitations: OS co-primary endpoint was not met (HR 0.88, P=.24), limiting the survival benefit interpretation. The PFS benefit is modest in absolute terms (medians 5.6 vs 5.6 months, though the HR is significant). Anemia is a class effect of HIF-2α inhibition and may require erythropoiesis-stimulating agent support or transfusion. Hypoxia events (8.6%) require monitoring, particularly in patients with baseline pulmonary conditions. Biomarker selection for HIF-2α pathway activation beyond ccRCC histology is not yet established.
Clinical Context
FDA approved belzutifan for previously treated advanced ccRCC in 2023. Belzutifan is the first HIF-2α inhibitor approved in oncology. In the post-immunotherapy + VEGF-TKI RCC landscape, belzutifan represents a novel mechanism beyond VEGF/mTOR. Ongoing trials evaluate belzutifan in first-line combinations and in other VHL-mutated cancers (VHL disease). Everolimus has largely been supplanted by belzutifan and cabozantinib in later-line ccRCC.
References
References: Choueiri TK et al, NEJM 2024