Targeting HIF‑2α and VEGF in Post-Immunotherapy RCC: Belzutifan + Lenvatinib Clinical Insights

Merck and Eisai announced that the combination of belzutifan (WELIREG) plus lenvatinib (LENVIMA) met the primary endpoint of progression-free survival (PFS) in the Phase 3 LITESPARK-011 trial in patients with previously treated advanced clear cell renal cell carcinoma (RCC) following anti-PD-1/PD-L1 therapy. The study demonstrated a statistically significant and clinically meaningful improvement in PFS, with higher objective response rates compared with cabozantinib, supporting the potential role of dual HIF-2α and VEGF pathway inhibition in the post-immunotherapy setting.

Drug Profile & Mechanism

• Belzutifan (WELIREG)
  • Profile: Oral hypoxia‑inducible factor‑2 alpha (HIF‑2α) inhibitor (first in class)
  • Mechanism: HIF‑2α is a transcription factor that drives expression of genes involved in angiogenesis and cell survival under hypoxic conditions; inhibition reduces tumor hypoxia adaptation and growth signals.
• Lenvatinib (LENVIMA)
  • Profile: Oral multi‑targeted tyrosine kinase inhibitor (VEGF receptors 1‑3, FGFR1‑4, PDGFRα, RET, KIT).
  • Mechanism: Disrupts tumor angiogenesis, proliferation, and tumor microenvironment support.
• Rationale for Combination: HIF‑2α inhibition may mechanistically complement anti‑angiogenic VEGF blockade by further suppressing hypoxia signaling and tumor vascular adaptation; this distinct dual targeting is hypothesized to improve disease control after immunotherapy failure.

LITESPARK‑011 Study Design (NCT04586231)

• Study Design: Phase 3, randomized, active-controlled, open-label trial
• Population: ~708 patients randomized ault patients with advanced clear cell RCC whose disease progressed after anti‑PD‑1/PD‑L1 immunotherapy.
• Arms:
  • Experimental: Belzutifan 120 mg orally once daily + Lenvatinib 20 mg orally once daily.
  • Control: Cabozantinib 60 mg orally once daily.
• Dual Primary Endpoints:
  • Progression‑Free Survival (PFS) by blinded independent central review per RECIST v1.1.
  • Overall Survival (OS) (protocol‑specified subsequent analysis).
• Key Secondary Endpoints:
  • Objective Response Rate (ORR) per RECIST v1.1.
  • Duration of Response (DOR).
  • Safety and tolerability.

Study Outcomes

Merck and Eisai have not yet publicly released the detailed numeric PFS data (median PFS in months, hazard ratio (HR), confidence intervals, or P‑values) for the LITESPARK‑011 trial.

• Primary Endpoint — PFS
  • The belzutifan + lenvatinib combination met the primary endpoint with a statistically significant and clinically meaningful improvement in PFS compared with cabozantinib in the targeted post‑immunotherapy advanced RCC population.
  • This is the first phase 3 data showing a HIF‑2α inhibitor combination achieving a positive PFS result in RCC.
• Key Secondary Enpoints:
  • ORR: Significantly higher with the combination versus cabozantinib (key secondary endpoint).
  • OS: Trend favoring belzutifan + lenvatinib observed, although it did not reach statistical significance at interim analysis; final OS evaluation to follow per protocol.
  • DOR: Assessed, with data expected upon fuller reporting.
  • Clinical relevance: Suggests potential benefit in post‑immunotherapy settings where few novel mechanisms have demonstrated phase 3 control

Regulatory Milestones

• Current & Near‑Term Regulatory Status
  • Topline announcement (October 2025): LITESPARK‑011 met PFS primary endpoint; sponsors plan data dissemination and discussions with global regulators.
  • FDA and EC approvals (2025): Belzutifan is already approved for selected advanced RCC and VHL indications, and regulatory filings for expanded use (including PPGL) have received priority review designations.
• Development Program Context
  • The LITESPARK program includes multiple phase 2/3 studies across RCC settings:
    • LITESPARK‑012: Belzutifan + pembrolizumab + lenvatinib in first‑line advanced RCC.
    • LITESPARK‑022: Adjuvant RCC (disease‑free survival endpoints).
    • Additional cohorts: PPGL and broader indications.
  • These data position belzutifan combinations as a potential new backbone after immunotherapy failure, pending regulatory review and publication.

Safety

• General Tolerability in LITESPARK‑011
  • No new safety signals compared with known profiles of belzutifan and lenvatinib; combination toxicities were consistent with individual compound safety profiles.
  • Expected adverse events with belzutifan (based on prior LITESPARK trials): anemia, hypoxia, fatigue, increased creatinine, headaches, nausea; anemia and hypoxia may require monitoring and interventions.
  • Known risks include embryo‑fetal toxicity; contraception guidance is required due to potential hormonal contraceptive interaction.
• Safety Context
  • Prior belzutifan monotherapy trials (e.g., LITESPARK‑004) reported high rates of decreased hemoglobin and anemia, hypoxia of varying grades, fatigue, and other class‑related toxicities. Mechanistic overlap with lenvatinib suggests vigilance for additive hematologic and vascular effects.

Clinical Implications

• Practice impact: If approved for post‑PD‑1/L1 therapy use, belzutifan + lenvatinib could address an unmet need in patients with advanced clear cell RCC following immunotherapy, offering a mechanistically novel combination beyond current VEGF‑TKI options.
• Efficacy: PFS benefit and improved ORR relative to cabozantinib support competitive positioning in later‑line therapy.
• Safety: Clinicians should monitor hematologic parameters and oxygenation, consistent with HIF‑2α inhibition and TKI toxicity profiles.
• Further data: Full peer‑reviewed results, OS outcomes, and safety breakdowns are anticipated at scientific meetings and in regulatory submissions.

Sources:

“Merck and Eisai Announce WELIREG® (Belzutifan) plus LENVIMA® (Lenvatinib) Met Primary Endpoint of Progression-Free Survival (PFS) in Certain Previously Treated Patients with Advanced Renal Cell Carcinoma – Merck.com.” Merck.com, 30 Dec. 2025, www.merck.com/news/merck-and-eisai-announce-welireg-belzutifan-plus-lenvima-lenvatinib-met-primary-endpoint-of-progression-free-survival-pfs-in-certain-previously-treated-patients-with-advanced-renal-c/. Accessed 30 Dec. 2025.

“A Study of Belzutifan (MK-6482) in Combination with Lenvatinib versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011).” Clinicaltrials.gov, 2025, clinicaltrials.gov/study/NCT04586231. Accessed 30 Dec. 2025.