FDA Approves Belzutifan for Advanced Pheochromocytoma and Paraganglioma

FDA

The 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.^1,2

The regulatory decision was supported by findings from the phase 2 LITESPARK-015 trial (NCT04924075), which showed that patients treated in cohort A1 (n = 72) achieved an overall response rate (ORR) of 26% (95% CI, 17%-38%) with belzutiafn. The median duration of response (DOR) was 20.4 months (95% CI, 8.3-not reached), with 53% of patients continuing to respond to treatment for at least 12 months. The median time to response (TTR) was 11.0 months (range, 1.7-24.8).

Moreover, 32% of patients (95% CI, 20%-45%) experienced a reduction in at least one antihypertensive medication by a least 50% maintained for at least 6 months.

In August 2021, the FDA approved belzutifan for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) that do not require immediate surgery.³

In December 2023, the regulatory agency also approved the agent for the treatment of patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF TKI.⁴

LITESPARK-015 Overview

The single-arm, open-label, international study evaluated the HIF-2α inhibitor in patients with advanced pheochromocytoma/paraganglioma and other advanced solid tumors.²

In cohort A1 of LITESPARK-015, eligible patients had histopathologically confirmed locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent therapy. They also needed to have controlled blood pressure defined as under 150/90 mm Hg or below 135/85 mm Hg for adolescents. For those with hypertension, there could not have been a change in antihypertensive medications for at least 2 weeks before belzutifan initiation. Those with carcinomatous meningitis were excluded.

Patients in the study received belzutifan at 120 mg once per day until disease progression or unacceptable toxicity.

ORR per RECIST 1.1 criteria, as assessed by blinded independent central review, served as the trial's primary end point. Secondary end points included DOR, TTR, and the proportion of patients who experienced a reduction in at least one antihypertensive medication by at least 50%, maintained for at least 6 months.

Safety Spotlight

The median duration of exposure to belzutifan was 20 months (range, 0.3-32.5). Serious toxicities were reported in 36% of patients. Dose reductions and interruptions due to adverse effects (AEs) were experienced by 14% and 40% of patients, respectively. Two patients experienced AEs that led to permanent treatment discontinuation of the drug.

The most common AEs experienced by at least 10% of patients who received belzutifan on the trial included anemia (all grade, 96%; grade 3/4, 22%), fatigue (56%; 10%), musculoskeletal pain (56%; 6%), dyspnea (33%; 1.4%), headache (29%; 1.4%), dizziness (26%; 2.8%), nausea (25%; 1.4%), edema (24%; 0%), constipation (24%; 1.4%), COVID-19 (17%; 2.8%), cough (15%; 0%), diarrhea (15%; 0%), decreased appetite (14%; 2.8%), muscle spasms (13%; 0%), muscle weakness (13%; 2.8%), hypoxia (13%; 10%), peripheral neuropathy (13%; 0%), abdominal pain (13%; 1.4%), increased weight (13%; 7%), arrhythmia (11%; 2.8%), nasal congestion (10%; 0%), vomiting (10%; 1.4%), hemorrhage (10%; 2.8%), and palpitations (10%; 0%).

Select laboratory abnormalities that occurred in at least 20% of patients and worsened from baseline in those who received the drug included decreased hemoglobin (all grade, 90%; grade 3/4, 21%), decreased lymphocytes (54%; 14%), increased alanine aminotransferase (51%; 4.2%), increased aspartate aminotransferase (42%; 4.2%), increased calcium (34%; 0%), increased potassium (31%; 2.8%), decreased leukocytes (30%; 0%), increased alkaline phosphatase (25%; 0%), decreased neutrophils (24%; 1.4%), increased creatinine (24%; 1.4%), decreased platelets (21%; 1.4%), and decreased sodium (21%; 0%).

References

1. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA. May 14, 2025. Accessed May 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma
2. Welireg. Prescribing information. Merck; 2025. Accessed May 14, 2025. https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdfhttps://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf
3. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. August 13, 2021. Accessed January 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease
4. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed January 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma