The LITESPARK-015 study (NCT04924075), a nonrandomized, multicenter global phase 2 pivotal clinical trial led by a team of researchers at The University of Texas MD Anderson Cancer Center and funded by Merck & Co. (Merck Sharp & Dohme/MSD outside the United States and Canada) showed significant tumor shrinkage and disease control in patients with advanced pheochromocytoma and paraganglioma (PPGL), two rare and potentially life-threatening neuroendocrine neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively.
While conventional treatment options, including surgery, radiation, and chemotherapy, are available, current management aims to control symptoms with medications, extend survival, and improve health-related Quality of Life (hrQoL), especially when a cure is not possible due to the spread of the cancer.
However, because most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2α (HIF-2α) pathway, recent research focuses on targeted therapies such as HIF-2α inhibitors and comprehensive genomic profiling to identify potential targets for personalized medicine.
Difficult to treat
Pheochromocytoma and paraganglioma (PPGL) are difficult-to-treat cancers that affect roughly 2,000 people annually in the United States. One of the main drivers of tumor growth in PPGL is the HIF-2α protein.
In healthy cells, this protein adjusts to changes in oxygen levels.
Still, genetic mutations or changes in cell metabolism can cause HIF-2α to become abnormally active, triggering signals that help the tumor grow and spread.
HIF-2α inhibitors, such as belzutifan (Welireg®; Merck & Co., previously known as MK-6482), have been successful in shrinking tumors and slowing disease progression in other cancers driven by HIF-2α overactivity, such as kidney cancer and von Hippel-Lindau (VHL) disease. Building on this knowledge, researchers evaluated the effectiveness of these inhibitors in patients with advanced PPGL.
Study
In the LITESPARK-015 Phase II trial, 72 patients with locally advanced, metastatic, unresectable PPGL who had exhausted all other standard-of-care treatment were treated with belzutifan.
The results of this study, led by Camilo Jimenez, M.D., professor of Endocrine Neoplasia and Hormonal Disorders, were published in the New England Journal of Medicine and presented concurrently at the European Society for Medical Oncology (ESMO) Congress, held October 17 – 21, 2025, in Berlin, Germany (Abstract 1705O).
A recent study showed that belzutifan, a HIF-2α inhibitor, demonstrated promising results in shrinking tumors and controlling disease in patients with advanced PPGL, leading to 58% of participants achieving stable disease.
Design
Patients participating in this study, aged ≥ 12 years, and diagnosed with progressive locally advanced, unresectable, or metastatic pheochromocytoma and paraganglioma, received 120 mg belzutifan QD until progression or unacceptable toxicity.
The primary endpoint was confirmed objective response rate (ORR) per RECIST 1.1 by blinded independent central review (BICR). Other key endpoints included duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per RECIST 1.1 by BICR, overall survival (OS), safety, and reduction in blood pressure (BP) medication.
Primary finding
In the LITESPARK-015 study, belzutifan showed meaningful antitumor activity with a 26% objective response rate, a significant achievement, particularly for rare and difficult-to-treat cancers. These effects lasted an average of more than 20 months, indicating a sustained clinical benefit for those who responded to treatment.
Furthermore, nearly one-third of patients (32%) who were taking blood pressure medication were able to reduce their dosage by half for at least six months. This is an important finding, as PPGL tumors often produce excess hormones that raise blood pressure. These results suggest that belzutifan may have also helped manage symptoms related to hormone-secreting tumors.
“The primary significance of this study is demonstrating that HIF-2α inhibition with belzutifan can achieve meaningful clinical benefit in patients with advanced, progressive PPGL,” Jimenez said.
“In a population with no remaining standard-of-care options, we observed durable disease control and a manageable safety profile, supporting the rationale for HIF-2α as a therapeutic target in this rare tumor type,” Jimenez added.
Regulatory status
In May 2025, the US Food and Drug Administration (FDA) approved belzutifan for the treatment of adult and pediatric patients ages 12 years and older with advanced, unresectable, or metastatic PPGL who do not require immediate surgery. Belzutifan is the first oral and only approved therapy for this disease, making it a new standard of care for this patient population.
“The approval of belzutifan offers new hope. As an oral treatment, it has been shown to shrink tumors, reduce symptoms, and improve quality of life with low toxicity. It represents a meaningful step forward in care for people living with these rare cancers,” Jimenez said.
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Clinical trials
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 ID NCT04924075
Highlights of Precribing Information
Belzutifan (Welireg®; Merck & Co)[Prescribing Information]
Reference
[1] Jimenez C, Andreassen M, Durand A, Moog S, Hendifar A, Welin S, Spada F, Sharma R, Wolin E, Ruether J, Garcia-Carbonero R, Fassnacht M, Capdevila J, Del Rivero J, Iliopoulos O, Huillard O, Jang R, Mai K, Artamonova E, Hallqvist A, Else T, Odeleye-Ajakaye A, Gozman A, Naik GS, Berruti A, for the LITESPARK-015 Investigators – Belzutifan for Advanced Pheochromocytoma or Paraganglioma NEJM October 18, 2025 DOI: 10.1056/NEJMoa2504964
Featured image ESMO 2018. Phoeto courtesy © 2018- 2025 ESMO.Ised with permission
DOI
, a nonrandomized, multicenter global phase 2 pivotal clinical trial led by a team of researchers at The University of Texas MD Anderson Cancer Center and funded by Merck & Co. (Merck Sharp & Dohme/MSD outside the United States and Canada) showed significant tumor shrinkage and disease control in patients with advanced pheochromocytoma and paraganglioma (PPGL), two rare and potentially life-threatening neuroendocrine neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively.){kind=link}