P3, N=450, Not yet recruiting, Merck Sharp & Dohme LLC

P2, N=32, Not yet recruiting, Dana-Farber Cancer Institute

As reported, ongoing phase III clinical trials are set to yield potentially practice-changing results, investigating innovative combinatorial strategies including belzutifan. Ongoing advancement of predictive biomarkers and understanding of resistance mechanisms could improve patient selection and identify new drug targets, thereby increasing the clinical efficacy of belzutifan.

By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.

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

Moreover, treatment with NKT2152 significantly reduced tumor growth in both cell line-derived and patient-derived xenograft models. In conclusion, our findings provide novel insights into the prognostic and functional role of HIF2A in ovarian CCC and underscore its potential as a promising therapeutic target.

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.

Although this molecular interaction may reflect SeMet-mediated attenuation of oxidative stress, biochemical data did not confirm changes in GSH/GSSG levels. These findings provide novel insights into the molecular mechanisms underlying MeHg neurotoxicity and its modulation by SeMet in fish brain, highlighting a potential protective role of organic Se against MeHg-induced molecular alterations.