Timing of Real-World Belzutifan-Related AEs Varies Between VHL-Associated Tumors and Sporadic RCC

Findings from a single-center retrospective analysis demonstrated that the time to onset and severity of adverse effects (AEs) related to belzutifan (Welireg) varied in patients with von Hippel-Lindau (VHL)–associated tumors vs those with sporadic, metastatic clear cell renal cell carcinoma (spRCC).¹

Data published in Oncologist by Aaron Jacob Winer, MD, and colleagues at Vanderbilt University Medical Center in Nashville, Tennessee, showed that any-grade anemia was reported in 81.8% of patients with spRCC (n = 22), including 41% who had grade 3 anemia. Among patients with VHL-associated tumors (n = 22), the rate of any-grade was 95.5%, although no patients experienced grade 3 anemia. The median time to onset of any-grade and grade 3 anemia in the spRCC cohort was 24 days (rang, 14-40) and 22 days (range, 21-43), respectively. The median time to onset of any-grade anemia was 77 days (range, 49-278) in the VHL cohort.

Furthermore, the rates of any-grade and grade 3 hypoxia were 59% and 54.5%, respectively, in the spRCC cohort; these respective rates were 13.6% and 9.1% in the VHL cohort. The median time to onset of any-grade and grade 3 hypoxia was 27 days (range, 21-41) and 29 days (range, 21-74), respectively, in the spRCC group; these respective figures were 105 days (range, 84-225) and 225 days (range, 165-285) in the VHL group.

“These findings underscore the need for a personalized approach to monitoring and managing patients taking belzutifan,” Winer and colleagues wrote. “Further studies are needed to help develop guidelines regarding follow-up strategies and toxicity management to best optimize patient outcomes.”

Winer is a member of the Division of Medicine Administration in the Department of Medicine at Vanderbilt University Medical Center.

What Was the Goals of Analyzing Differences in Safety Outcomes With Belzutifan?

Belzutifan, which is an HIF-2ɑ inhibitor, is currently approved for the treatment of adult patients with VHL disease who require therapy for associated RCC, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery; and for adult patients with advanced RCC with a clear cell component following a PD-1 or PD-L1 inhibitor and a VEGF TKI.² Notably, the agent’s received an additional indication in May 2025, when the FDA approved its use for adult and pediatric patients 12 years of age and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma.³

With the agent still relatively new to clinical practice following its initial approval in the VHL space in 2021, investigators of the real-world study sought to better understand the AE profile of belzutifan when administered to the VHL and spRCC patient populations in everyday practice.¹

The study included patients at least 18 years of age who were treated with single-agent belzutifan for either spRCC or a VHL-associated tumor at any stage or line of therapy. Patients given the agent as part of a combination and those lost to follow-up were excluded from the analysis; a median follow-up of 1.5 months was required for each patient included.

Patients were identified via a pharmacy query for all belzutifan prescriptions filled at Vanderbilt from August 30, 2021, to August 30, 2024.

The primary end point of the analysis was the incidence of any-grade and grade 3 or higher anemia and hypoxia. Secondary end points related to anemia and hypoxia comprised time to onset, need for supplemental erythropoietin-stimulating agent(ESA) and/or blood transfusion, dose reductions, treatment interruptions, treatment discontinuation, and hospitalization.

In the VHL cohort, 45.5% of patients had bilateral RCC, 22.7% had unilateral RCC, 86.4% had CNS hemangioblastoma, 59.1% had retinal hemangioma, and 50% had pNET.

The median age was 41 years (interquartile [IQR] range, 33-54) in the VHL cohort vs 67 years (IQR, 62-71) in the spRCC cohort. Most patients in the VHL cohort were female (63.6%), compared to the spRCC cohort, which was primarily male (68.2%). All patients other than 1 in the VHL cohort and 2 in the spRCC cohort had an ECOG performance status of 0 or 1. Baseline characteristics such as comorbidities, supplemental oxygen use, smoking history, and hemoglobin levels were similar between the 2 arms.

In the spRCC group, 36.4% of patients had at least 3 metastatic sites, with the most common included lung (90.4%), lymph node (40.9%), bone (40.9%), adrenal (22.7%), and liver (13.6%). Patients in this group received a median of 3 prior lines of therapy (range, 1-7); 95.5% of patients received a prior immune checkpoint inhibitor, and immune checkpoint inhibitor–based combinations were the most common prior line of therapy, reported in half of patients in this group.

The median follow-up was 27 months (IQR, 21-29) in the VHL cohort vs 4 months (IQR, 2-5) in the spRCC cohort. The median duration of therapy was 31 months (IQR, 22-33) and 3 months (IQR, 2-6), respectively.

How Were Belzutifan-related AEs Managed in the VHL and spRCC Cohorts?

Pooled data between the 2 cohorts showed that among patients who experienced anemia, 11.4% received an ESA alone, 6.8% were given blood transfusions alone, and 1 patient (2.3%) received both. Anemia led to withholding of belzutifan in 31.8% of patients, and 20.5% required dose reductions due to anemia. The median time to anemia resolution was 28 days (range, 1-434).

In the management of hypoxia, 29.5% of patients to experience the AE needed supplemental oxygen, and 25% required hospitalization. Hypoxia led to dose reductions, treatment interruption, and treatment discontinuation in 50%, 70.5%, and 31.8% of patients, respectively.

In the spRCC cohort, AEs led to treatment dose reductions in 40.9% of patients, dose interruptions in 72.7% of patients, and treatment discontinuation in 50% of patients. These respective rates were 59.1%, 68.2%, and 13.6% in the VHL cohort.

“Limitations of this study include differences in follow-up intervals, which may have introduced detection bias. Additionally, [patients with] spRCC underwent more frequent clinical and laboratory evaluations than [patients with] VHL, who often had longer follow-up overall,” study authors concluded. “A multivariable analysis would help disentangle the independent effects of baseline characteristics, but our limited sample size and retrospective design precluded the approach; future larger cohorts with sufficient power will be necessary to perform these analyses.”

References

1. Winer AJ, do Amaral PS, Ryan EG, et al. The safety profile of belzutifan in renal tumors: real-world data from a tertiary academic center. Oncologist. Published online September 8, 2025. doi:10.1093/oncolo/oyaf274
2. Welireg. Prescribing information. Merck. Updated May 2025. Accessed September 24, 2025. https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf
3. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA. May 14, 2025. Accessed September 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma