Welireg (belzutifan)

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.

Radiopharmaceuticals such as 131I-MIBG and 177Lu-DOTATATE continue to play a pivotal role, achieving disease control in many patients. Cytotoxic regimens, particularly temozolomide, remain relevant, with some studies suggesting that SDHB-mutated PPGLs demonstrate a heightened sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression. Targeted agents are increasingly important: multi-kinase inhibitors such as sunitinib, anlotinib, and cabozantinib have shown meaningful activity. The landmark approval of belzutifan, a HIF-2α inhibitor, in 2025 represents the first oral targeted therapy for advanced/metastatic PPGL, which is particularly relevant for pseudohypoxic Cluster 1 tumors...This review summarizes current evidence and highlights ongoing clinical trials, underscoring a paradigm shift toward precision medicine and rational combination strategies. Collectively, these advances bring cautious optimism that metastatic PPGLs may soon become a more manageable chronic disease with improved survival and quality of life.

In treatment, radioligand therapy (PRRT) is used earlier in appropriate receptor-positive disease; cabozantinib improves progression-free survival after prior therapy; and belzutifan offers a biomarker-guided option for malignant pheochromocytoma/paraganglioma...We appraise strengths and limitations of key trials, note issues of access and toxicity, and highlight active areas in development (SSTR antagonists, alpha emitters, and dose-guided PRRT). Our goal is to provide a concise, evidence-based map of the field to support informed clinical judgment and future research priorities.

Relative standard deviations (RSD) were below 2%, indicating precision and reproducibility. Owing to its simplicity and efficiency, the method is suitable for routine quality control in pharmaceutical laboratories.

These findings indicate that the p.E92G ELOC variant is responsible for the VHL manifestations in this family, and that these tumors are being driven by loss of the VCB-Cul2 E3-ubiquitin ligase complex activity.

P3, N=904, Not yet recruiting, Merck Sharp & Dohme LLC