- Results from the LITESPARK-015 open-label, multicohort phase 2 trial show that hypoxia-inducible factor-2 alpha inhibitor belzutifan achieves durable antitumor activity in patients with advanced paraganglioma. Findings from this study supported the FDA fast-track approval in this patient population, representing an important development in precision oncology for these rare cancers.
- Paragangliomas are rare neuroendocrine tumors that are typically slow-growing, however approximately 55% of patients eventually develop metastasis, for whom therapeutic options are limited.
- The molecular characterization of these tumors unraveled the critical role of HIF-2α in cancer progression and metastasis, therefore serving as a potential therapeutic target.
- Concomitantly published in The New England Journal of Medicine, data from a LITESPARK-015 cohort study, co-authored by Jaume Capdevila, Medical Oncologist at the Vall d’Hebron University Hospital and Head of VHIO’s Hepatobiliary Pancreatic Cancer and Endocrine Tumors Group, were presented today at the 2025 European Society for Medical Oncology (ESMO) Annual Congress, 17 – 21 October, Berlin.
The international, open-label, single-arm, multi-cohort phase 2 LITESPARK-015 trial evaluated the efficacy and safety of the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan in patients with unresectable or metastatic paraganglioma.
Co-authored by Jaume Capdevila, Medical Oncologist at the Vall d’Hebron University Hospital and Head of VHIO’s Hepatobiliary Pancreatic Cancer and Endocrine Tumors Group, follow-up data from the LITESPARK-015 cohort 1A study show that at a median of 30.2 months, objective response rate (ORR) was 26.4%, with a median duration of response (DOR) of 20.4 months. The safety profile of belzutifan was consistent with prior trials, showing manageable adverse events.
“Results from this study supported the fast-track approval by the U.S. Food and Drug Administration of belzutifan for eligible patients with advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. This represented the first FDA approval of an oral therapy for this patient population1 and marked an important milestone in precision oncology for these rare tumors2,” said Jaume Capdevila.
Results from LITESPARK-015 were presented today at a Proffered Paper session of the 2025 European Society for Medical Oncology (ESMO) Annual Congress3, 17 – 21 October, Berlin, by first author Camilo Jimenez, Professor, Department of Endocrine Neoplasia and Hormonal Disorders, the University of Texas MD Anderson Cancer Center, and published simultaneously in The New England Journal of Medicine4.
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors (NETs) originating in the adrenal medulla and the extra-adrenal sympathetic or parasympathetic paraganglia, respectively. Incidence of PPGL is about 6 cases per million people annually with approximately 10% of cases diagnosed in childhood.
“Approximately 25% of patients will eventually develop metastasis. These patients have a lower rate of survival and high degree of morbidity due to tumor burden, disease progression, and excessive secretion of catecholamines that can lead to cardiovascular and gastrointestinal complications. The 5-year survival rate after initial diagnosis in patients with metastatic paraganglioma is around 60%, underscoring the need to identify and develop new biomarker-based treatment strategies,” explained Capdevila.
The translation of emerging research into targeted therapy
“Researching rare cancers presents unique challenges including accessing samples, identifying novel biomarkers or preclinical models and, in many cases, limited funding,” said Rodrigo A. Toledo, Head of VHIO’s Biomarkers and Clonal Dynamics Group.
Over recent years, international collaboration between consortia including the European Network for the Study of Adrenal Tumours (ENS@T) and the A5 Alliance (American Australian Asian Adrenal Alliance), as well as support from foundations such as the Paradifference Foundation and patient associations including the Pheo Para Alliance and Asociacion Pheipas, has fostered and accelerated research into paragangliomas.
“Comprehensive genomic characterization allowed us to identify the HIF2α protein as a key driver in the tumorigenesis and metastasis of paraganglioma. More than 20 genes are associated with this tumor type, highlighting the presence of alterations in the EPAS1 gene, which encodes the HIF2α protein,” added Toledo.
Based on these genetic and epidemiological observations, the pheochromocytoma and paraganglioma (PPGL) research community soon recognized the therapeutic potential of inhibiting HIF2α.
Over 50% of patients achieved stable disease
Belzutifan is a HIF2α inhibitor currently approved for treating adults with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma and other NETs, and is also approved in the U.S. for the treatment of advanced renal cell carcinoma in combination with immunotherapy.
LITESPARK-015 evaluated the efficacy and safety of belzutifan in a total of 72 patients. At a median follow-up of 30.2 months ORR was 26.4%, and 58.3% of patients achieved stable disease, resulting in an overall disease control rate (DCR) of 8.7%. Notably, responses were durable, with a median duration of 20.4 months, and 64.2% or responders maintained their response for at least 12 months. Median progression-free survival (PFS) was 22 months, and a median overall survival has not been reached.
Clinical benefit in tumor-related symptoms was further supported by sustained reduction in total daily dose of antihypertensive medication, with approximately one-third of participants who received antihypertensive medication having a decrease equal to or greater than 50% in the total daily dose.
“These data, together with a manageable safety profile, led the FDA to approve belzutifan for this patient population, representing a first step toward positioning this HIF-2α as first-line therapy for these patients whose treatment options are currently limited. This milestone exemplifies how collaboration between academia and industry can translate into new therapeutic options for patients with rare tumors such as paragangliomas,” concluded Capdevila.
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References
1. FDA approves belzutifan for pheochromocytoma or paraganglioma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma
- Arenillas C, Toledo RA. FDA fast-track approval of belzutifan is a milestone in rare cancer therapy. Nat Rev Endocrinol. 2025 Sep 11. doi: 10.1038/s41574-025-01183-z. Epub ahead of print. PMID: 40935878.
- ESMO Congress 2025, 17 – 21 October, Berlin
Corresponding session details:
Date : 18 October, 2025
Chairs : Chris Verslype (Leuven, Belgium) Rachel Riechelmann (Sao Paulo, Brazil)
Room: Karlsruhe Auditorium – Hall 5.2
Session time: 10:15 – 11:45 (CEST)
Abstract: 1705O – LITESPARK-015: Belzutifan in advanced pheochromocytoma and paraganglioma
Speaker: Camilo Jimenez
Lecture time: 10:25 – 10:35 (CEST)
- Camilo Jimenez, M.D.; Mikkel Andreassen, M.D., Ph.D.; Alice Durand, M.D.; Sophie Moog, M.D., Ph.D.; Andrew Hendifar, M.D.; Staffan Welin, M.D.; Francesca Spada, M.D., Ph.D.; Rohini Sharma, M.B.B.S., Ph.D.; Edward Wolin, M.D.; Joseph Ruether, M.D.; Rocío García-Carbonero, M.D.; Martin Fassnacht, M.D.; Jaume Capdevila, M.D., Ph.D.; Jaydira del Rivero, M.D.; Othon Iliopoulos, M.D.; Olivier Huillard, M.D.; Raymond Jang, M.D.; Knut Mai, M.D.; Elena Artamonova, M.D., Ph.D.; Andreas Hallqvist, M.D.; Tobias Else, M.D.; Amos Odeleye-Ajakaye, M.S.; Alexander Gozman, M.D.; Girish S. Naik, M.D., M.M.Sc.; Alfredo Berruti, M.D., en representación de los investigadores del estudio LITESPARK-015. Belzutifan in Advanced Pheochromocytoma or Paraganglioma. N Engl J Med. DOI: 10.1056/NEJMoa2504964
