Belzutifan Granted FDA Approval for Pheochromocytoma or Paraganglioma

Belzutifan is the first oral therapy approved for PPGL.

The FDA has granted its first approval of an oral therapy for pheochromocytoma or paraganglioma (PPGL) to belzutifan (Welireg) for the treatment of adult and pediatric patients aged 12 years or older with locally advanced, unresectable, or metastatic disease, according to an announcement from the FDA.¹

Efficacy and Safety Data

The objective response rate (ORR) for belzutifan in patients with PPGL was 26% (95% CI, 17%-38%; n = 72). The median duration of response (DOR) for these patients was 20.4 months (95% CI, 8.3-NR). Out of 60 patients who were taking antihypertensive medications at intake, 19 (32%; 95% CI, 20%-45%) had a reduction of at least 50% in at least 1 antihypertensive medication sustained for 6 months or longer.

The efficacy of belzutifan was evaluated in the multi-cohort, open-label LITESPARK-015 trial (NCT04924075) in patients PPGL. The primary trial end points were ORR and DOR, along with the number of patients with a reduction in one or more antihypertensive medications of at least 50% for at least 6 months.

The most common adverse events (AEs), which were reported in at least 25% of patients, including laboratory abnormalities, were anemia, fatigue, musculoskeletal pain, lymphocytopenia, increased alanine aminotransferase, increased aspartate aminotransferase, hypercalcemia, dyspnea, hyperkalemia, leukopenia, headache, increased alkaline phosphatase, dizziness, and nausea.

Belzutifan is recommended at 120 mg administered orally once a day for adults and pediatric patients 12 or older weighing at least 40 kg. Pediatric patients whose weight is less than 40 kg should receive 80 mg orally once daily. Treatment should be continued until disease progression or unacceptable toxicity.

The drug’s prescribing information includes warnings for anemia, hypoxia, and embryo-fetal toxicity.² Such AEs may result in discontinuation of treatment. Female patients who are able to become pregnant are advised to use effective hormonal birth control during the time of treatment and for 1 week after. The same is advised for female partners of male patients with reproductive potential.

Trial Inclusion and Exclusion Criteria

LIGHTSPARK-015 is evaluating the use of belzutifan in patients with PPGL, pancreatic neuroendocrine tumors (pNET), von Hippel-Lindau (VHL) disease, or advanced wild-type gastrointestinal stromal tumor (GIST) or advanced solid tumors with HIF-2α-related genetic alterations.³

Patients with carcinomatous meningitis were excluded from the study. Those with concomitant hypertension and adequately controlled blood pressure were eligible to participate, so long as they had no changes in their antihypertensive medications for at least two weeks prior to study initiation.¹

Background on Belzutifan and PPGL

The FDA granted priority review to the drug’s supplemental new drug application (sNDA) for use in PPGL on January 27, 2025, per an announcement from its developer, Merck & Co., Inc. At that time, the approval’s target date was May 26, 2025.⁴

According to the announcement, PPGL can occur due to certain genetic mutations or syndromes and as many as 25% of cases are metastatic when diagnosed. Approximately 2,000 cases are diagnosed in the US per year, and 52,800 are diagnosed globally per year. While paraganglioma occur in nerve tissue in the adrenal glands and near certain nerves and blood vessels, pheochromocytoma occur in the center of the adrenal gland.

The announcement also states that full efficacy information will be presented at an upcoming medical conference.

Belzutifan was approved for use in advanced renal cell carcinoma (RCC) that has progressed on on December 14, 2023 and for use in von Hippel-Lindau (VHL)-associated RCC, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) on August 14, 2021.^5,6

References

1. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA. May 14, 2025. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma
2. Belzutifan. Prescribing information. Merck & Co., Inc.; December 2023. Accessed May 14, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215383s006lbl.pdf
3. Belzutifan/​MK-6482 for the Treatment of Advanced Pheochromocytoma/​Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015). ClinicalTrials.Gov. June 11, 2021. Updated May 6, 2025. Accessed May 14, 2025. https://clinicaltrials.gov/study/NCT04924075#study-record-dates
4. FDA Grants Priority Review to Merck’s Application for WELIREG® (belzutifan) for the Treatment of Patients With Advanced Pheochromocytoma and Paraganglioma (PPGL). News release. Merck & Co., Inc. January 27, 2025. Accessed May 14, 2025. https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-welireg-belzutifan-for-the-treatment-of-patients-with-advanced-pheochromocytoma-and-paraganglioma-ppgl/
5. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma
6. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. News release. Accessed May 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease