Welireg (belzutifan)

P1/2, N=37, Not yet recruiting, M.D. Anderson Cancer Center

P1/2, N=60, Active, not recruiting, Merck Sharp & Dohme LLC | N=210 --> 60

The recent approval of the HIF2 inhibitor belzutifan represents a landmark advance, yet both primary and acquired resistance remain major barriers...We also discuss translational opportunities, including HIF2 inhibitor combinations with CDK4/6 inhibitors and anti-VEGF agents, and highlight CCND1/CCND2 as potential biomarkers. Finally, we outline future challenges and perspectives for precision-based, mechanism-driven therapy in ccRCC.

This review consolidates 2023-2025 advances: phase III validation in post-IO/TKI ccRCC (progression-free survival and response-rate gains vs. everolimus), durable first-line activity with cabozantinib, and approval for advanced pheochromocytoma/paraganglioma-including patients ≥ 12 years-extending impact to endocrine and pediatric oncology...Caution is appropriate: overall survival benefit in randomized RCC trials is not yet demonstrated, resistance can emerge, and long-term hematologic and pulmonary effects require surveillance. Together, HIF-2α inhibition establishes a new, clinically actionable axis in GU oncology.

On the translational front, HIF-2α inhibitors (such as belzutifan), strategies that suppress or oxidize lipids to trigger ferroptosis, and interventions targeting glutamine and one-carbon metabolism show promise when rationally combined with ICIs, TKIs, or anti-angiogenic therapies. We propose a stratified decision framework anchored in DCCD state, lipid-droplet/PLIN2 phenotype, ferroptosis sensitivity, and HIF activity, and discuss the emerging roles of radiopathomics (e.g., CT HU-PLIN2 coupling) and circulating metabolic fingerprints in companion diagnostics. Looking toward clinical deployment, advancing standardization within MSI/IBSI and FAIR data principles-and launching biomarker-enriched, prospective multicenter trials-will be essential to demonstrate the real-world value of precision metabolic oncology in the personalized treatment of ccRCC.

This approval, which is based on the results of the pivotal Phase 2 clinical trial MK-6482-004 (LITESPARK-004) 1,2,3 offers a therapeutic approach to managing certain VHL disease-associated tumours. This article describes the clinical data supporting belzutifan approval, in the EU, focusing on the VHL disease indication and its mechanism of action.

P2, N=10, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Subgroup analysis showed higher efficacy of HIF-2α inhibitors (belzutifan) compared to VEGFR inhibitors (62% vs. 44%; 95% CI: 49-74 and 30-59, respectively)...Targeted therapy focusing on the molecular pathogenesis of VHL-associated RCC provides meaningful disease control while preserving renal function. HIF-2α inhibitors demonstrate superior efficacy and lower toxicity compared with VEGFR-targeted agents, representing a promising non-surgical alternative for managing VHL-related RCC.

P1, N=45, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Oct 2026 --> Jun 2027 | Trial primary completion date: Oct 2026 --> Jun 2027

P3, N=904, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

The method demonstrated successful clinical validation through analysis of plasma samples from rats, achieving excellent correlation with reference LC-MS/MS methods while providing real-time therapeutic drug monitoring capabilities. This represents the first fluorometric approach for belzutifan quantification and establishes a new paradigm for anticancer drug monitoring that combines the advantages of carbon dot nanotechnology with clinically relevant near-infrared detection, offering significant potential for point-of-care therapeutic drug monitoring in oncology practice.

Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma.