Belzutifan for HIF2A-Related Pheochromocytoma and Paraganglioma: A Retrospective Study of Real-World Data.

Objectives: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors of the adrenal medulla and autonomic ganglia, respectively. Germline and somatic genetic drivers are identified in up to 70% of cases. Hypoxia-inducible factor 2α (HIF-2α), encoded by the EPAS1 (HIF2A) gene, plays a central role in PPGL pathogenesis and can be stabilized directly or indirectly by pathogenic variants of several genes, collectively called pseudohypoxia cluster (or Cluster 1). Belzutifan, a small-molecule HIF-2α inhibitor, has demonstrated efficacy in von Hippel-Lindau (VHL)-related cancers, renal cell carcinoma, and few case reports of PPGL. We report real-world outcomes of belzutifan therapy in five patients with recurrent, multifocal, or metastatic EPAS1(HIF2A)-related PPGL.

Methods: Clinical parameters, biochemical markers, tumor burden (RECIST 1.1), and treatment-related adverse events were carefully monitored, and recorded.

Results: Four of five patients (80%) achieved a partial response, and one patient had stable disease, with no disease progression to date. The average reduction in the sum of tumor diameters was 36.8%. Chromogranin A, erythropoietin, and hemoglobin declined by 69%, 97%, and 13%, respectively, eliminating the need for therapeutic phlebotomy in patients with prior erythrocytosis. Catecholamine normalization allowed discontinuation or reduction of antihypertensive medications in two patients. Adverse events included hypoxia and anemia (1/5), mild transaminase elevation (2/5), and fatigue with weight gain (1/5).

Conclusions: Belzutifan is a highly effective and well-tolerated therapeutic option for EPAS1(HIF2A)-related PPGL, producing substantial biochemical and radiographic responses, improved blood pressure control, and resolution of erythrocytosis. These findings support belzutifan as a promising genotype-driven therapy for pseudohypoxia-driven PPGL.