Belzutifan Receives Priority Review in Pheochromocytoma/Paraganglioma

Data from the phase 2 LITESPARK-015 trial support the sNDA for belzutifan in patients with pheochromocytoma or paraganglioma.

The FDA has accepted for priority review a supplemental new drug application (sNDA) for belzutifan (Welireg), an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, in adult and pediatric patients with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma (PPGL), according to a press release from the developer, Merck.¹ A Prescription Drug User Fee Act date of May 26, 2025 has been set.

Belzutifan is currently the only HIF-2α inhibitor therapy approved in the US for the treatment of adult patients with von Hippel-Lindau (VHL) disease who need therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery.² Additionally, belzutifan is approved in the US and Canada for the treatment of patients with RCC who had a PD-1/PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).³

Results from the phase 2 LITESPARK-015 trial (NCT04924075) that evaluated belzutifan monotherapy in patients with PPGL, pancreatic neuroendocrine tumors, VHL disease-associated tumors, advanced gastrointestinal stromal tumors, and advanced solid tumors informed the FDA’s decision.

“Pheochromocytoma and paraganglioma are rare tumors that form in and around the adrenal glands, and currently, there are no approved therapies available in the 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 the press release.¹ “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.”

Overall response rate (ORR) and duration of response (DOR) data from the PPGL cohort of the LITESPARK-015 trial supported the sNDA and will be presented at a future medical congress.

The trial enrolled an estimated 322 patients, and in the PPGL cohort, inclusion criteria included documented histopathological diagnosis of PPGL with no limit on the number of prior systemic therapies.⁴ Additionally, patients had to have locally advanced or metastatic disease unamenable to surgery or curative intent treatment and adequately controlled blood pressure (150/90 mm Hg or less for adults and 135/85 mm Hg or less for adolescents) with no change in antihypertensive medications at least 2 weeks prior to study treatment.

All patients were assigned to receive 120 mg of oral belzutifan once daily.

Patients were excluded if they were unable to swallow orally administered medication or had a disorder that would affect absorption of belzutifan. Other exclusion criteria included having a history of second malignancy, unless a patient underwent curative treatment with no evidence of malignancy for 2 years.

The trial’s primary end point is ORR assessed by blinded independent central review (BICR). Secondary end points include DOR per BICR, time to response, disease control rate, progression-free survival, overall survival, number of patients experiencing adverse events (AEs), number of patients discontinuing study drug due to an AE, and time to surgery.

Although not highlighted in a PPGL indication, current belzutifan labeling cites anemia and hypoxia as potential AEs of concern, as well as embryo-fetal toxicity in pregnant women.⁵

In the LITESPARK-004 trial (NCT03401788) that evaluated belzutifan in patients with VHL disease who had at least 1 measurable solid tumor in the kidney, decreased hemoglobin was observed in 93% of patients, and 7% had grade 3 events. Hypoxia was observed in 1.6% of patients. In the LITESPARK-005 trial (NCT04195750) that evaluated belzutifan in patients with RCC who progressed after PD-1/PD-L1 or VEGF receptor targeted therapies, 88% of patients had decreased hemoglobin, and 29% had grade 3 events. Hypoxia occurred in 15% of patients, and 10% had grade 3 events.

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://tinyurl.com/5x5ta339
2. FDA approves Merck’s hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor WELIREG™ (belzutifan) for the treatment of patients with certain types of von Hippel-Lindau (VHL) disease-associated tumors. News release. Merck. August 13, 2021. Accessed January 27, 2025. https://tinyurl.com/5n93s49a
3. FDA approves Merck’s WELIREG® (belzutifan) for the treatment of patients with advanced renal cell carcinoma (RCC) following a PD-1 or PD-L1 inhibitor and a VEGF-TKI. News release. Merck. December 14, 2023. Accessed January 27, 2025. https://tinyurl.com/27wd42e5
4. 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. Updated December 27, 2024. Accessed January 27, 2025. https://tinyurl.com/5zmfyejx
5. Prescribing information. WELIREG® (belzutifan) tablets, for oral use. FDA. 2021. Accessed January 27, 2025. https://tinyurl.com/bdf3dce8