Belzutifan Approved for Advanced Pheochromocytoma and Paraganglioma
Expert Perspectives · Lyn Brook · 2025-05-15
The FDA has granted approval to belzutifan (Welireg®, Merck & Co., Inc.) for the treatment of adult and pediatric patients aged 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL). This marks the first FDA approval of an oral therapy for PPGL, providing a new treatment option for patients with these rare neuroendocrine tumors.
Why This Approval Matters
Pheochromocytoma and PPGL are rare tumors that form in the adrenal gland and outside the adrenal gland, respectively. They can be caused by certain genetic syndromes or mutations, including von Hippel-Lindau disease (VHL). The approval of belzutifan represents a significant advancement for patients with advanced PPGL, a population with limited therapeutic options. As the first oral agent approved for this indication, belzutifan offers an alternative to traditional therapies, potentially improving both disease control and quality of life for affected patients.
Breaking Down the LITESPARK-015 Trial
Efficacy for belzutifan was established in the LITESPARK-015 trial (NCT04924075), an open-label, multi-cohort study. Cohort A1 enrolled 72 patients with measurable, histopathologically confirmed PPGL that was locally advanced or metastatic and not amenable to surgery or curative treatment. Disease status was verified by blinded independent central review (BICR) using RECIST v1.1 criteria. Patients with controlled hypertension were eligible, provided their antihypertensive regimen remained stable for at least two weeks prior to study entry. Those with carcinomatous meningitis were excluded.
The primary efficacy end point was objective response rate (ORR) as assessed by BICR. Secondary end points included duration of response (DOR) and the proportion of patients achieving a sustained reduction in antihypertensive medication. Belzutifan produced an ORR of 26%, indicating that more than a quarter of patients experienced a significant reduction in tumor burden. The median DOR was 20.4 months, suggesting durable responses in many patients. Among the 60 patients on baseline antihypertensive therapy, 19 achieved at least a 50% reduction in one or more antihypertensive medications, maintained for at least six months.
Managing Adverse Events
The most common adverse events experienced in ≥25% of patients, including laboratory abnormalities, were anemia, fatigue, musculoskeletal pain, decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased calcium, dyspnea, increased potassium, decreased leukocytes, headache, increased alkaline phosphatase, dizziness, and nausea.
Dosing and Administration
The recommended dose for adults is 120 mg of belzutifan orally once daily. For pediatric patients aged 12 years and older, dosing is weight-based: those weighing ≥40 kg should receive 120 mg once daily, while those weighing <40 kg should receive 80 mg once daily. Treatment should continue until disease progression or unacceptable toxicity.
Clinical Implications and Future Outlook
The approval of belzutifan provides an oral treatment option for patients with advanced PPGL. The demonstrated efficacy and manageable safety profile support its use as a new standard of care for eligible patients. Ongoing research will further clarify its role in the management of these rare tumors and may expand its use to additional patient populations in the future.