Behind the FDA Approval: Belzutifan for VHL-Associated Renal Cell Carcinoma

Eric Jonasch, MD

In August of 2021, the FDA approved Belzutifan (Welireg), a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for adult patients with von Hippel-Lindau (VHL) disease who require therapy for renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery. Snice’s it’s approval, the agent has had a major impact on this patient population.

According to Eric Jonasch, MD, a professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, patients with VHL disease face a lifetime of surveillance and surgery. Having an agent that is able to reduce the number of surgeries a patient has is of paramount importance.

Belzutifan was approved based on results of a phase 2 study (NCT03401788) enrolling 61 patients. The study found the agent to not only be effective, but also to have a manageable safety profile.

In an interview with Targeted Oncology^TM, Jonasch discussed the impact belzutifan has had on the VHL space, along with unmet clinical needs the agent is addressing.

TARGETED ONCOLOGY: Can you discuss belzutifan and how it’s used to treat this patient population?

JONASCH:Belzutifan is a HIF-2α inhibitor. What that means is that a lot of VHL-related cancers like clear cell renal cell carcinoma and other tumors, they have a defect in VHL protein function and VHL regulates HIF-2α levels and if you have broken VHL, you have high levels of HIF-2α. HIF-2α is a transcription factor, and it results in the transcription of a number of genes that regulate metabolism, that regulate angiogenesis, regulate cell survival. And so, the consequence of having loss of VHL function and upregulation of HIF-2α is excess production of these transcription factors, which really result in a very angiogenic microenvironment in tumor. The belzutifan drug is an agent that can actually bind to HIF-2α, prevent it from heterodimerizing with its partner HIF-1 beta, and that way you stop the transcription that would occur from inappropriate high levels of HIF-2α.

What data support this FDA approval?

This was a 61-patient study. It was an international study, it was a single arm study, which is a little unusual, but when you look at the rarity of VHL disease, there's probably about 10,000 people with VHL disease in United States, it's a little more understandable. The most recent data were presented at American Society of Clinical Oncology 2021. And there we had a median follow up of 22 months in the 61-patient study, the primary end point was objective response rate in VHL disease associated renal cell carcinoma, and the secondary end points were objective response rate and non RCC neoplasms.

These 61 patients had a median age of about 41, pretty even split between men and women. And none of them had metastatic disease because this was not a study to look for metastatic disease. It was a study to try to prevent the growth of these multi-focal bilateral renal cell carcinomas that arise in this hereditary patient population.

The primary end point was met, the objective response rate to confirm the objective response rate was 49%. And there were several at the time of data cutoff unconfirmed responses. Fifty-four patients at the time that this was reported remained on steady. A very few came off for progression. Most patients came off for personal choices, there was actually 1 death from a non-drug or disease related event. And the progression-free survival has not been met. And more importantly, what we started seeing is we start seeing also that, for example, in pancreatic lesions, most patients actually had some pancreatic lesion, seeing an objective response rate of 77% with some complete responses. The pancreatic neuroendocrine tumors that we're seeing also in about 22 of these patients, we saw an objective response rate of 90%. And in central nervous system hemangioblastomas, which aren't cancers per se, but are very problematic for this patient population, we saw an objective response rate of 30%. Similarly, also these patients will get retinal hemangioblastomas as well, which are triplet usually treated laser therapy and the majority of these also demonstrated response. So, we're seeing that all of these VHL deficiency related tumors in this patient population are exhibiting response both for the primary end point as well as for the secondary end points.

Can you describe the safety safety profile of this agent?

The major toxicity or the major side effect that was seen was anemia. Those individuals who did develop anemia were managed fairly well. Some had transfusions, but more and more as, as investigators became comfortable with the agent and the management of the agent, we started using erythropoietin. And that was highly effective at regulating the anemia. There are also a few patients that had to just by laboratory or by pulse oximetry measured hypoxemia. But that was usually transient, and none of the patients required any treatment discontinuation and it wasn't anything that that they were actually particularly symptomatic, for. So that those were the major toxicities and the agent was actually fairly well tolerated.

What unmet need is belzutifan meeting?

At this point in time, patients with Von Hippel Lindau disease really face a lifetime of surveillance with that with imaging studies and various other modalities, followed by interventions. When at an organ level they start running into problems, for example, the eyes they would require laser treatment. If they get an endolymphatic sac tumor in the middle ear, they would require a surgery, if their cerebellar and spinal hemangioblastomas get too large, they would require surgery. The renal cell carcinomas would require surgery or ablation, the pancreatic neuroendocrine tumors would require surgery, and the pheochromocytomas might require surgery. Some of these individuals literally have dozens of surgeries throughout their entire lives. And the both the physical and emotional burden of the anticipatory anxiety and the anticipatory exam anxiety of dealing with these potential complications is really challenging. And not only that, when surgery does occur, there's consequences of surgery, there's, there's pain from that. There's loss of productivity, loss of time at work.