FDA Grants Priority Review to Belzutifan for Advanced Pheochromocytoma and Paraganglioma

The FDA has granted priority review to a supplemental new drug application (sNDA) seeking the approval of belzutifan (Welireg) for the treatment of adult and pediatric patients 12 years of age and older with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma.1

The sNDA is supported by data from the phase 2 LITESPARK-015 trial (NCT04924075), which was a single-arm study investigating the agent in patients with pheochromocytoma/paraganglioma and other advanced solid tumors. Data from the study will be presented at an upcoming medical meeting, according to an announcement from Merck.

The FDA assigned the sNDA a target action date of May 26, 2025, under the Prescription Drug User Fee Act.

“Pheochromocytoma and paraganglioma are rare tumors that form in and around the adrenal glands, and currently, there are no approved therapies available in the United States [US] for patients with this rare disease,” Marjorie Green, MD, senior vice president and head of Oncology, Global Clinical Development, at Merck Research Laboratories, stated in a news release. “Today’s US filing acceptance demonstrates our commitment to advancing novel therapies, such as [belzutifan], to help treat patients with certain rare oncologic diseases. We look forward to working with the FDA to potentially provide this critical option to these patients who urgently need new innovative therapies.”

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.2

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.3

LITESPARK-015 Spotlight

Investigators of the open-label, multi-cohort, international study enrolled patients 12 years of age or older with advanced pheochromocytoma and paraganglioma (cohort A1), pNETs (cohort A2), VHL-associated tumors (cohort B1), advanced gastrointestinal stromal tumors (cohort C), or advanced solid tumors with HIF-2α–related genetic alterations (cohort D).1,4

In cohort A1, patients were required to have a histopathological diagnosis of locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent therapy.4 Enrolled patients were allowed to receive belzutifan as first-line therapy if a satisfactory treatment option was not available; patients who were not candidates for or refused systemic chemotherapy were also allowed to enroll. There was no limit on prior systemic therapies. Locoregional therapies and (neo)adjuvant therapies were not considered prior lines of systemic therapy. Patients also needed to have adequately controlled blood pressure with no change in antihypertensive medications within 2 weeks of study enrollment.

The study protocol allowed patients with a history of VHL disease to enroll in cohort A1 if concurrent lesions were localized without immediate need for intervention. Prior surgical resection(s) for concurrent localized VHL-associated tumors were permitted if there was no history of metastatic disease from the concurrent tumors; however, prior systemic therapy for these concurrent tumors was not allowed. The presence of CNS metastases and/or carcinomatous meningitis, along with significant cardiovascular disease, excluded patients from enrolling.

Patients enrolled in cohort A1 and all other cohorts received belzutifan at 120 mg once per day until disease progression or discontinuation.

Blinded independent central review (BICR)–assessed objective response rate per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included BICR-assessed duration of response, time to response, disease control rate, and progression-free survival; overall survival; safety; and time to surgery.

References

1. 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. January 27, 2025. Accessed January 27, 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/
2. 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
3. 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
4. Belzutifan/​MK-6482 for the treatment of advanced pheochromocytoma/​paraganglioma (ppPPGLgl), 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. Updated December 27, 2024. Accessed January 27, 2025. https://clinicaltrials.gov/study/NCT04924075