FDA Approves the First Oral Drug for Pheochromocytoma and Paraganglioma: Belzutifan

On May 14, 2025, the US Food and Drug Administration (FDA) approved belzutifan (brand name Welireg, Merck & Co.) for the treatment of adult and pediatric patients aged 12 years or older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL) .

This approval is notable because it provides, for pheochromocytoma or paraganglioma the first oral treatment option .

What Are Pheochromocytoma and Paraganglioma?

Pheochromocytoma and paragangliomaare tumors originating in the nervous system that are rare and usually hormone-producing . Pheochromocytomas arise in the adrenal glands, while paragangliomas develop elsewhere in regions containing nerve cells, such as the neck, chest, or abdomen. These tumors are particularly associated with excessive production of hormones that control blood pressure , such as adrenaline, and can cause severe hypertensive crises. Untreated, they may cause both local complications and distant metastases.

The LITESPARK-015 Study: Belzutifan Efficacy and Findings

The FDA approval is based on LITESPARK-015 , an open-label, multicohort clinical study. Cohort A1involved 72 patients with unresectable or metastatic pheochromocytoma or paraganglioma and measurable disease.

Key Findings:

• Objective response rate (ORR): 26% (95% CI: 17–38)

• Duration of response (DOR): median 20.4 months (95% CI: 8.3, not reached)

• Of 60 patients taking antihypertensive medication, 19 (32%)achieved a 50% dose reduction in at least one medication, lasting at least 6 months.

Adverse Reactions:

The most frequently reported adverse reactions with belzutifan were:

• Anemia (low red blood cell count) (83%)

• Fatigue (32%)

• Musculoskeletal pain, dizziness, shortness of breath

• Elevated liver enzymes, headache, nausea, hypoxia, and calcium and potassium imbalances

Dose and Administration

• In adults, the recommended dose is: 120 mg/day (oral)

• In children ≥40 kg: 120 mg/day

• In children <40 kg: 80 mg/day
  Treatment continues until disease progression or intolerable toxicity.

About Belzutifan (Welireg) and Previous FDA Approvals

Belzutifan, a HIF-2α inhibitor , is an orally administered targeted agent developed to prevent tumor growth driven by hypoxia.

FDA Approvals:

1. August 13, 2021 – Von Hippel-Lindau (VHL) disease-associated tumors

2. December 14, 2023 – RCC (kidney cancer) progressing after a PD-1/PD-L1 inhibitor + VEGF-TKI

3. May 14, 2025 – Pheochromocytoma / Paraganglioma (PPGL) → First oral treatment approval

Mechanism of Action:

• By blocking excessive activity of the hypoxia-responsive HIF-2α protein, it:

  • Slows tumor growth

  • Inhibits new blood vessel formation

  • Suppresses tumor-cell survival pathways

Status in Türkiye:

• Not yet licensed in Türkiye.

• May be obtained from abroad with special authorization.

Conclusion and Clinical Interpretation

For rare but potentially life-threatening tumors such as pheochromocytoma and paraganglioma, approval of an oral targeted agentis an important clinical advance. Belzutifan stands out for its positive effects not only on disease control but also on blood pressure regulation .

This development further strengthens the role of HIF-2α-targeted therapies in cancer treatment and offers a promising option, particularly for patients with a genetic predisposition.