Key takeaways
1. Regulatory milestone for rare tumors: Merck’s Welireg received FDA approval for treating advanced PPGL in patients aged 12+, marking the first non-surgical treatment option for this rare condition and highlighting the importance of regulatory strategy in rare oncology indications.
2. Strong clinical endpoint performance: The Phase II LITESPARK-015 trial demonstrated a 26% objective response rate and a median 20.4-month duration of response, emphasizing the value of well-designed, multicohort studies in achieving expedited approval.
3. Broader implications for trial design: Welireg’s multiple approvals across rare tumors and RCC illustrate the benefit of using adaptive, multicenter trial designs (e.g., LITESPARK series) to support expanded indications and demonstrate therapeutic versatility.
The FDA has approved Merck’s Welireg (belzutifan) for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL). The approval is based on data from the Phase II LITESPARK-015 clinical trial (NCT04924075).1
LITESPARK-015 results and trial design
Welireg, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, demonstrated positive outcomes in LITESPARK-015. The primary endpoint of objective response rate (ORR) was met at 26%. Additionally, Welireg showed a median duration of response (DOR) of 20.4 months. Further results showed 19 of the 60 patients on baseline antihypertensive medications had a reduction in at least one antihypertensive medication by at least 50% for at least six months.2
In a press release, Camilo Jimenez, MD, professor, department of endocrine neoplasia and hormonal disorders, The University of Texas MD Anderson Cancer Center, said: “PPGL, sometimes referred to as pheo para, is a rare condition affecting up to 2,000 people each year in the United States. Patients with these tumors, which arise from the adrenal glands and the extra-adrenal paraganglia, may require specialized care due to their complexity and rare nature, often posing significant challenges for both diagnosis and treatment. This approval, which is based on objective response rate data from the LITESPARK-015 trial, introduces belzutifan as the only approved and available non-surgical option for locally advanced, unresectable, or metastatic PPGL and could represent a change to the treatment paradigm for eligible patients.”
LITESPARK-015 is an open-label, multicohort trial. The study enrolled 72 patients in Cohort A1 and received WELIREG at a dose of 120 mg once daily until disease progression or unacceptable toxicity. In addition to the endpoints of ORR and DOR, the study evaluated time to response.
In the press release, Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, added: “For patients with advanced PPGL, there has been a lack of approved systemic treatment options available to help manage their disease, underscoring the importance of this approval in the US. This approval marks the third indication for Welireg in the US and demonstrates our company’s commitment to providing innovative cancer therapies for patients in need, including those with rare diseases.”
Welireg’s prior FDA approval for the treatment of advanced renal cell carcinoma
This most recent indication for Welireg in PPGL follows another FDA approval for renal cell carcinoma (RCC). Announced in December 2023, this approval was based on results from the randomized, open-label, Phase III LITESPARK-005 trial (NCT04195750).3
In a press release from the time, Green said: “In 2021, Welireg became the first HIF-2α inhibitor therapy approved in the US for the treatment of adult patients with certain VHL disease-associated tumors and is now approved for eligible patients with advanced RCC. This approval of Welireg marks the first new therapeutic class available for eligible patients with advanced RCC in nearly a decade, and was based on the statistically significant progression-free survival benefit observed in patients following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI when compared to everolimus.”
LITESPARK-005 trial results
In LITESPARK-005, Welireg was compared to Novartis’ Afinitor (everolimus) for the treatment of advanced RCC that has progressed after prior treatment with PD-1/L1 and VEGF-TKI therapies, either in sequence or in combination. The trial showed that Welireg produced a statistically significant improvement in survival compared to Afinitor, lowering the risk of disease progression or death by 25%.
References
1. FDA Approves Merck’s WELIREG® (belzutifan) for the Treatment of Adults and Pediatric Patients 12 Years and Older With Locally Advanced, Unresectable, or Metastatic Pheochromocytoma or Paraganglioma (PPGL). News release. Merck. May 14, 2025. Accessed May 16, 2025. https://www.merck.com/news/fda-approves-mercks-welireg-belzutifan-for-the-treatment-of-adults-and-pediatric-patients-12-years-and-older-with-locally-advanced-unresectable-or-metastatic-pheochromocytoma-or-par/
2. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA. May 14, 2025. Accessed May 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma
3. LITESPARK-005 Trial Data Lead to FDA Approval of Welireg for Advanced Renal Cell Carcinoma. Applied Clinical Trials. December 23, 2023. Accessed May 16, 2025. https://www.appliedclinicaltrialsonline.com/view/litespark-005-trial-data-lead-to-fda-approval-of-welireg-for-advanced-renal-cell-carcinoma
