FDA Approves Belzutifan in Advanced Pheochromocytoma and Paraganglioma

• The FDA has granted approval to belzutifan (Welireg) for the treatment of patients aged 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma and paraganglioma (PPGL).
• Data from the phase 2 LITESPARK-015 trial (NCT04924075) support this approval.
• This marks the first approval from the FDA of an oral therapy for PPGL.

The FDA has approved belzutifan for the treatment of adult and pediatric patients 12 years of age and older with locally advanced, unresectable, or metastatic PPGL, marking the first FDA approval of an oral therapy for this patient population.¹

Efficacy findings from the LITESPARK-015 trial support this FDA approval. Cohort A1 of the study included 72 patients with measurable disease that was verified by blinded independent central review (BICR) per RECIST v1.1, documented histopathological PPGL diagnosis, and locally advanced or metastatic disease not amenable to surgery or curative treatment. For the primary end point of objective response rate (ORR) by BICR using RECIST v1.1, ORR was 26% (95% CI, 17%-38%) with belzutifan in this cohort.

Additional end points assessed in the study were duration of response (DOR) and the number of patients who had a reduction in 1 or more antihypertensive medication by at least 50% maintained for at least 6 months. The median DOR in this cohort was 20.4 months (95% CI, 8.3-not reached). Further, 19 of the 60 patients on baseline antihypertensive medications (32%) had a reduction in at least 1 antihypertensive medication by at least 50% for at least 6 months (95% CI, 20%-45%).

Looking at safety, anemia, fatigue, musculoskeletal pain, decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased calcium, dyspnea, increased potassium, decreased leukocytes, headache, increased alkaline phosphatase, dizziness, and nausea were the most common adverse reactions (≥25%) observed in the study.

With this approval, the recommended dose of belzutifan for adult patients with PPGL has been set at 120 mg administered orally once a day. For pediatric patients 12 years of age and older, the recommended dose is based on body weight. Pediatric patients who weigh ≥ 40 kg will be given belzutifan at a dose of 120 mg orally once daily, and pediatric patients weighing < 40 kg will be given at a dose of 80 mg orally once daily. Belzutifan should be continued until disease progression or unacceptable toxicity, according to the FDA.

About the LITESPARK-015 Trial

Cohort A1 of LITESPARK-015 trial included patients with advanced PPGL, 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.^2,3

Cohort A1 included patients with a confirmed diagnosis of locally advanced or metastatic PPGL, that could not be treated with surgery or curative-intent therapy.² Patients with concomitant hypertension with adequately controlled blood pressure were required to have no change in antihypertensive medications for 2 weeks or more before study initiation. This cohort excluded patients with carcinomatous meningitis. Here, patients were eligible to receive belzutifan as a first-line treatment if no other effective options were available.

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

Those with a history of VHL disease were also eligible to join cohort A1 if 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, but prior systemic therapies for these tumors were not permitted.

In August 2021, the FDA approved belzutifan for adult patients with VHL disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pNETs not requiring immediate surgery. 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 approves belzutifan for pheochromocytoma or paraganglioma. News release. FDA. May 14, 2025. Accessed May 14, 2025. https://tinyurl.com/2hr8pu2r

2. 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 May 14, 2025. https://tinyurl.com/ydyhj8z4

3. 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 May 14, 2025. https://clinicaltrials.gov/study/NCT04924075