Belzutifan induced durable responses without surgery in patients with advanced pheochromocytoma or paraganglioma and demonstrated manageable safety in the phase II LITESPARK-015 trial, according to findings presented during the European Society for Medical Oncology (ESMO) Congress 2025 (Abstract 1705O) and published in The New England Journal of Medicine.
“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,” said Camilo Jimenez, MD, Professor of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center. “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.”
Rationale and Study Methods
Most cases of metastatic PPGL are driven by dysregulation of the HIF-2α pathway, and belzutifan is a HIF-2α inhibitor, showing its potential for efficacy in these tumor types.
The international, single-group phase II LITESPARK-015 trial included 72 patients with locally advanced or metastatic PPGL that was not amenable to surgery or curative-intent treatment. Patients received 120 mg of belzutifan once daily.
Key Study Findings
The confirmed objective response rate was 26% (95% confidence interval [CI] = 17%–38%) and the disease control rate was 85% (95% CI = 74%–92%). The median duration of response was 20.4 months (95% CI = 8.3 months to not reached) and the median duration of progression-free survival was 22.3 months (95% CI = 13.8 months to not reached). The 24-month overall survival rate was 76%, and the median overall survival was not yet reached.
Sixty patients were receiving antihypertensive medication, and 32% of these patients required a dose reduction of belzutifan by at least 50% in the total daily dose of at least one of their antihypertensive drugs for at least 6 months after starting on the therapy.
Treatment-related adverse events were reported in 99% of patients, with grade 3 anemia notably observed in 22% as the most common adverse event. Serious treatment-related adverse events were reported in 11% of patients; grade 3 events were observed in 46% of patients, and grade 4 events in 3%, while no grade 5 events were reported. Fourteen percent of patients required a dose reduction and 3% discontinued treatment due to adverse events.
The FDA approved belzutifan for the treatment of adult and pediatric patients aged 12 years and older with advanced, unresectable, or metastatic PPGL who do not require surgery immediately in May 2025.
“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,” Dr. Jimenez said.
Disclosure: The study was supported by Merck Sharp & Dohme LLC. For full disclosures of the study authors, visit nejm.org.
