FDA Approval of Belzutifan Provides Needed Option in Pheochromocytoma or Paraganglioma

Clinical presentations for pheochromocytoma and paraganglioma can manifest as hypertension due to excess catecholamine, which may be exacerbated by treatment with TKIs, according to Kimberly Perez, MD.

In May 2025, the FDA expanded the label for belzutifan (Welireg),1 making it the first and only approved oral therapy for patients with pheochromocytoma or paraganglioma. The HIF-2α inhibitor, which is also approved for patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, pancreatic neuroendocrine tumors that do not require immediate surgery, and advanced RCC following a PD-(L)1 inhibitor and VEGF TKI,2 does not carry the same risk for hypertension as TKIs, making the agent an equally effective and potentially safer option for patients, Perez said.

“The take home is that these are exciting results. This [approval] is game-changing for this patient population. We now have another FDA-approved treatment option that will be widely available to…community as well as academic providers, which is amazing,” Perez said in an interview with OncLive®.

In the interview, Perez discussed the significance of the approval, the clinical advantages of the agent, and the importance of continued research in this rare patient population. 

Perez is the codirector of Clinical Research in the Division of Gastrointestinal Oncology and a senior physician at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What is the significance of the FDA approval of belzutifan for patients with pheochromocytoma or paraganglioma?

Perez: [The significance is] tremendous. This is a rare tumor type, and the treatment options are somewhat limited. The only FDA-approved treatment option had been iobenguane I 131 [Azedra], but it’s no longer manufactured or available. The fact that we now have an FDA-approved drug option [with belzutifan] that was prospectively evaluated in a very strong clinical trial is great, and it will mean a lot to patients and providers.

How does the agent’s mechanism of action differ from other treatments available to this population?

Traditionally, like any other cancer, chemotherapy [is a treatment option], which is the traditional [means of] trying to interrupt cell growth. In the past couple of decades, we have moved into the targeted therapy [realm], and…we’ve been evaluating and turning to TKIs for treatment outside of chemotherapy. Then there are the radiopharmaceuticals like MIBG [iodine-123 meta-iodobenzylguanidine] or iobenguane I 131, as well as lutetium Lu 177 dotatate [Lutathera], which has been evaluated.

Belzutifan is different because it’s a HIF-2α inhibitor, so the protein that it’s going after is different than what has been investigated in the past.

What was the impetus for the pivotal phase 2 LITESPARK-015 trial (NCT04924075)?

The trial was designed to evaluate the role of belzutifan in patients with VHL disease in the initial cohort. VHL status was not necessary in the cohort that included patients [with pheochromocytoma and paraganglioma]. There are molecular pathways that are involved with the development of parathyroid [tumors], and this pathway happens to be one that is affected or involved in a good number of [patients]. [For that reason] the use of the drug and the efficacy [we’ve seen] makes sense.

Trying to collect as much information prospectively as we can is exactly what we should all be doing when it comes to these rare tumor groups. With the initial molecular biomarker [driving the research] and then opening it up to other cohorts based on what we know about the different pathways for a disease like this is exactly how trials should be conducted.

What efficacy and safety data were reported with the agent?

A lot of the treatments, or the treatments that we’ve used more commonly in parathyio have been TKIs and chemotherapy. The adverse effect profiles with chemotherapy are well known. With TKIs the concern that’s been raised is the risk of hypertension, and hypertension, for some of our patients, is the predominant clinical presentation for the disease, because it’s associated with catecholamine excess. The fact that belzutifan doesn’t have that risk profile is significant for this patient population.

In terms of [efficacy], we’re seeing similar response rates to the few prospective trials with TKIs, but to have similar response rates in addition to a more manageable toxicity profile is really appealing and a real success for this patient population.

What advice would you give someone who wants to integrate this agent into their practice?

Like anything else, it’s [important to] use the information and the safety data that are available from all the tumor types that were involved in this trial. [Another important aspect is] making sure that clinical assessments are happening on a routine schedule and [that we’re] utilizing the dose schedules that were evaluated in the trial, and [keeping an eye on the potential need for] dose modifications as you would with any other treatment.

References

1. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA. May 14, 2025. Accessed September 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma
2. Welireg. Prescribing information. Merck Sharp & Dohme; 2024. Accessed September 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215383Orig1s007lbl.pdf