FDA Grants Belzutifan Priority Review For Advanced Pheochromocytoma and Paraganglioma

• The FDA granted priority review to a supplemental new drug application (sNDA) seeking the approval of belzutifan (Welireg) for the treatment of patients aged 12 years and older with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma.
• Data from the phase 2 LITESPARK-015 trial (NCT04924075) support this sNDA.
• A target action date of May 26, 2025, under the Prescription Drug User Fee Act (PDUFA) has been set.

The FDA has granted priority review to a sNDA seeking belzutifan’s (Welireg) approval for the treatment of adult and pediatric patients 12 years of age and older with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma. With this approval, the sNDA has been assigned a target action date of May 26, 2025, under the PDUFA.

Objective response rate (ORR) and duration of response (DOR) data from the phase 2 LITESPARK-015 trial (NCT04924075), a single-arm trial evaluating belzutifan for the treatment of patients with pheochromocytoma/paraganglioma and other advanced solid tumors, support this sNDA.

Findings from the study are expected to be presented at an upcoming medical meeting.

“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, said in a press 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.”

The open-label, multi-cohort, international study included patients aged 12 years or older and stratified them into the following cohorts: Cohort A1 included patients with advanced pheochromocytoma and paraganglioma, cohort A2 included patients with pancreatic neuroendocrine tumors (pNETs), cohort B1 included patients with von hippel-lindau disease (VHL)-associated tumors, cohort C included patients with advanced gastrointestinal stromal tumors, and cohort D included patients with advanced solid tumors with HIF-2α–related genetic alterations.^1,2

In cohort A1, patients needed a confirmed diagnosis of locally advanced or metastatic pheochromocytoma or paraganglioma, that could not be treated with surgery or curative-intent therapy.² Patients were eligible to receive belzutifan as a first-line treatment if no other effective options were available.

Those who were ineligible for systemic chemotherapy or chose to decline it were also allowed to participate. There were no restrictions based on prior systemic treatments, though locoregional and (neo)adjuvant therapies did not count as prior systemic therapies. Patients had to have stable blood pressure with no changes in antihypertensive medications for at least 2 weeks prior to enrollment.

The study also allowed individuals with a history of VHL disease to join cohort A1, provided their VHL-associated lesions were localized and did not require immediate treatment. Surgical resections for localized VHL-associated tumors were acceptable as long as there was no history of metastatic spread from these tumors. However, prior systemic therapies for these tumors were not permitted.

Participants in cohort A1, as well as those in other cohorts, received belzutifan at a dosage of 120 mg once daily, continuing until disease progression or the decision to discontinue treatment.

The primary end point of the trial was blinded independent central review (BICR)–assessed ORR per RECIST 1.1 criteria. Secondary end points consisted of BICR-assessed DOR, time to response, disease control rate, and progression-free survival; overall survival; safety; and time to surgery.

Previously in August 2021, the FDA granted approval to belzutifan for the treatment of adult patients with VHL disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pNETs not requiring immediate surgery.Then in December 2023, the agent was approved by the FDA for the treatment of patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor.

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 28, 2025. https://tinyurl.com/ydyhj8z4

2. 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 28, 2025. https://clinicaltrials.gov/study/NCT04924075