Background
Phase 3, open-label RCT (N=747; 184 centers, 25 countries) of belzutifan (HIF-2α inhibitor) plus lenvatinib (VEGFR TKI) vs cabozantinib in advanced/metastatic clear-cell RCC with progression on or after anti-PD-(L)1 therapy (adjuvant, first-line, or second-line; prior VEGFR TKI allowed). First phase 3 trial of a HIF-2α inhibitor + TKI combination in RCC. Randomized 1:1, stratified by IMDC risk score, line of prior immunotherapy, and geographic region.
Results
Interventions and follow up: Arm A: Belzutifan 120 mg PO daily + lenvatinib 20 mg PO daily, until progression or unacceptable toxicity
Arm B: Cabozantinib 60 mg PO daily, until progression or unacceptable toxicity
Primary endpoint: Dual — PFS by BICR (RECIST 1.1) and OS
mFollow up: 29.0 months (second interim analysis)
Results: PFS: 14.8 vs 10.7 mo; HR 0.70 (95% CI 0.59–0.84); P<.0001
OS: 34.9 vs 27.6 mo; HR 0.85 (95% CI 0.68–1.05); P=.061 — not significant at second interim; follow-up ongoing
ORR: 53% vs 40%
mDOR: 23.0 vs 12.3 mo
Arm B: Cabozantinib 60 mg PO daily, until progression or unacceptable toxicity
Primary endpoint: Dual — PFS by BICR (RECIST 1.1) and OS
mFollow up: 29.0 months (second interim analysis)
Results: PFS: 14.8 vs 10.7 mo; HR 0.70 (95% CI 0.59–0.84); P<.0001
OS: 34.9 vs 27.6 mo; HR 0.85 (95% CI 0.68–1.05); P=.061 — not significant at second interim; follow-up ongoing
ORR: 53% vs 40%
mDOR: 23.0 vs 12.3 mo
Adverse events
Grade ≥3 TEAE: 84% vs 83%
Hypertension G≥3: 31% vs 29% (most common G≥3 event in both arms)
Treatment-related deaths: 2 vs 1
Safety profile: consistent with the known profiles of the individual drugs; no new signals
Hypertension G≥3: 31% vs 29% (most common G≥3 event in both arms)
Treatment-related deaths: 2 vs 1
Safety profile: consistent with the known profiles of the individual drugs; no new signals
Conclusions
Belzutifan plus lenvatinib significantly prolonged PFS and improved ORR and duration of response over cabozantinib, an active contemporary TKI, in post-immunotherapy advanced ccRCC. This is the first phase 3 RCC trial to beat a modern VEGFR TKI comparator and supports HIF-2α-based combinations as a potential new second-line standard, pending OS maturation.
Key Limitations
Open-label design. OS co-primary endpoint not met at second interim analysis (HR 0.85; P=.061). Doublet-vs-monotherapy design leaves the contribution of each component unclear (lenvatinib-based therapy is itself active post-ICI). 87% of participants were White, limiting generalizability. Grade ≥3 events in >80% of both arms; tolerability of the doublet in routine practice unknown. Post-ICI population was heterogeneous (prior TKI exposure allowed; adjuvant to second-line immunotherapy).
Clinical Context
Current post-ICI options include cabozantinib (METEOR), lenvatinib + everolimus, and tivozanib (TIVO-3). Belzutifan monotherapy is FDA-approved (Dec 2023, LITESPARK-005) for advanced RCC after ICI and VEGFR-TKI. An sNDA for belzutifan + lenvatinib in previously treated advanced RCC is under FDA review with a target action date of October 4, 2026; the combination is not yet approved. NCCN currently lists belzutifan monotherapy as a subsequent-line option; a positive FDA decision would position this doublet as a new second-line standard after anti-PD-(L)1 therapy.