The U.S. Food and Drug Administration (FDA) has approved belzutifan (Welireg) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. The approval, announced on May 14, 2025, marks a significant advancement for patients with these rare tumors, as belzutifan becomes the first oral therapy specifically approved for these conditions.
The approval was based on compelling data from the phase 2 LITESPARK-015 trial (NCT04924075), which evaluated belzutifan in patients with advanced disease. In cohort A1 (n = 72), the agent demonstrated a confirmed overall response rate of 26% (95% CI, 17%-38%) with a median duration of response of 20.4 months (95% CI, 8.3-not reached).
A Critical Advancement for Rare Tumors
Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that develop in the adrenal glands or outside the adrenal glands, respectively. These tumors are often associated with catecholamine excess, which can lead to hypertension and other serious complications.
"The fact that we now have an FDA approved drug option that was prospectively evaluated in a very strong clinical trial is great, and I think it will mean a lot to patients and providers of this patient population," said Dr. Kimberly Perez, a medical oncologist and co-director of clinical research in the Division of Gastrointestinal Oncology at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School.
Dr. Perez emphasized that prior to this approval, systemic treatment options for pheochromocytoma and paraganglioma were extremely limited. The only previously approved agent, iobenguane I 131 (Azedra), is no longer commercially available. Alternative therapies—including tyrosine kinase inhibitors (TKIs) and cytotoxic chemotherapy—have been used in this population but are associated with notable toxicity concerns, particularly in patients with catecholamine-secreting tumors where hypertension is a dominant clinical feature.
Novel Mechanism of Action
Belzutifan operates through a novel mechanism as a selective hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. This approach differs significantly from historically used regimens and addresses a key concern in treating these patients.
Dr. Perez noted that the absence of exacerbated hypertensive events associated with belzutifan is clinically meaningful given the underlying biology of these tumors and their association with catecholamine excess. This characteristic makes belzutifan particularly valuable for this specific patient population.
Safety Profile and Dosing
Belzutifan was generally well tolerated in the LITESPARK-015 trial. The most frequently reported adverse effects—occurring in at least 25% of patients—consisted of:
- Anemia
- Fatigue
- Musculoskeletal pain
- Decreased lymphocyte and leukocyte counts
- Elevated alanine aminotransferase, aspartate aminotransferase, calcium, potassium, and alkaline phosphatase levels
- Dyspnea
- Dizziness
- Headache
- Nausea
The recommended dosage of belzutifan is 120 mg once daily for adult patients and pediatric patients weighing at least 40 kg. For pediatric patients weighing under 40 kg, the recommended dose is 80 mg once daily. Treatment should continue until disease progression or the development of unacceptable toxicity.
Clinical Implications
This approval represents a significant advancement in the treatment landscape for patients with pheochromocytoma and paraganglioma. The oral administration route offers convenience compared to intravenous therapies, potentially improving quality of life for patients with these rare tumors.
The durable responses observed in the clinical trial suggest that belzutifan may provide meaningful clinical benefit for patients who previously had few effective treatment options. Additionally, the manageable safety profile makes it a viable option for long-term treatment in appropriate patients.
Healthcare providers now have a new tool in their armamentarium for treating these challenging tumors, with a therapy that has demonstrated efficacy in a prospective clinical trial specifically designed for this patient population.
