HIF-2 alpha inhibitors are transforming therapy for patients with renal cell carcinoma and von Hippel-Lindau disease.
Sean Korbitz had his first bout with cancer — a brain tumor discovered after six months of nausea and vomiting — in 2007. Since then, the 36-year-old has had multiple surgeries and procedures on 40 brain tumors and is under surveillance for 12 tumors in his pancreas, three on his spine and several lesions on his kidneys, which doctors are treating as renal cell carcinoma.
Before that first brain tumor in 2007, the Denver-based media professional had no idea that he carried a gene mutation that would cause him to get tumors again and again throughout his body for his entire life.
With von Hippel- Lindau (VHL) disease, he could expect to live to approximately age 60 at best and to spend his now-limited years in and out of the hospital for dozens of, or even a hundred, surgeries to remove tumors.
“In my case, it was going to be guaranteed brain surgeries. It was so traumatic,” Korbitz says. “It affects everything in your life: relationships, your physical body, career. Everything is completely affected for months, years and sometimes a decade. I’m still dealing with issues from my 2007 brain surgery.”
When Korbitz eventually developed lesions on his kidneys, which were found in 2016 during the routine scans that people with VHL disease undergo every
year, doctors told him there was nothing they could do yet. Surgery would compromise his kidney function, and there weren’t any approved drugs for renal cell carcinoma caused by VHL disease.
His care team would monitor the growths until one of the tumors measured at least 3 centimeters — a sign that the cancer was likely to spread soon — and then they would surgically remove as many and as much of the tumors as they could.
But that care plan changed last year when Welireg (belzutifan), a first-in-class targeted drug known as a hypoxia-inducible factor-2 (HIF-2) alpha inhibitor, was approved by the Food and Drug Administration (FDA) to stop this exact kind of kidney cancer in its tracks.
HIF-2 alpha inhibitors are bringing new hope to people with cancers caused by VHL disease, and they are also showing promise for clear cell renal cell carcinomas in people who do not have VHL disease.
“I think these drugs are a game changer,” says Dr. Eric Jonasch, a professor of medicine at The University of Texas MD Anderson Cancer Center in Houston
and lead investigator on the Welireg clinical trial that earned the drug’s recent FDA approval. “Like tyrosine kinase inhibitors in 2005 and checkpoint antibodies in the mid-20-teens, I think this is the next sea change in treatment of renal cell carcinoma.”
A mutation in the VHL gene is the primary driver of most clear cell renal cell carcinomas, both in people with and without the genetic VHL disease. Clear cell renal cell carcinoma accounts for about 3 out of 4 cases of kidney cancer.
People who have VHL disease carry a mutation in the VHL gene that is part of their own DNA. Those who don’t have the disease but who develop clear cell renal cell carcinoma typically have mutations in the VHL gene as well in their tumors, but in their cases, the mutation is acquired in the affected cells in the kidney and not in all the cells of the body.
A normal VHL gene produces VHL protein, which interacts with hypoxia-inducible factor (HIF) protein when oxygen levels are normal, but uncouples from HIF when oxygen levels fall, thereby functioning as an oxygen sensor.
A mutated cell, on the other hand, lacks functional HIF, which prevents cells from sensing oxygen. The cell inappropriately senses a low-oxygen state (known as hypoxia) and accumulates HIF-2 alpha. This protein, in turn, sets off a cascade of cancer- promoting processes down the line.
“Accumulation of this protein activates downstream processes that allow for cell growth and angiogenesis — that’s the (formation) of new blood vessels,” explains Dr. Kristen Millado, a hematologist and medical oncologist at Baptist Health Miami Cancer Institute.
“In kidney cancer, inappropriate production of these downstream proteins allows for the overgrowth of cells and carcinogenesis.”
People with renal cell carcinoma are treated with drugs such as Sutent (sunitinib malate), Cometriq (cabozantinib) and Inlyta (axitinib) that block angiogenesis, which is one of the downstream cancer-promoting processes that high HIF-2 alpha causes.
“Combination targeted therapy and immunotherapy really changed the paradigm of kidney cancer treatment in the last five years,” Millado says. “And now, HIF-2 alpha inhibitors offer another novel approach.”
HIF-2 alpha inhibitors latch onto the HIF-2 alpha protein and prevent it from triggering damaging downstream processes in the first place.
Last year, the FDA approved Welireg, the first HIF-2 alpha inhibitor for the treatment of renal cell carcinoma, central nervous system hemangioblastomas and pancreatic neuroendocrine tumors in people who have VHL disease. The approval was based on initial results from an ongoing clinical trial in which half of patients with renal cell carcinoma responded to the drug.
“We saw that tumors decreased in size, and in a small percentage of individuals, we saw complete disappearance of tumors. So it’s clearly decreasing the number of tumor cells,” explains Jonasch.
More than half of the patients who had a response to the drug continued to respond for more than a year. Many are still doing well on the therapy today, Jonasch says.
Korbitz started taking Welireg in October 2021, just a couple months after its FDA approval. He has now been on the drug for a year. Each scan that he has had during that time has shown a 20% to 50% reduction in the size of the tumors on his kidneys, pancreas and spinal cord.
The only tumor that has not changed is the one that doctors continue to watch in his brain. Brain and spinal cord tumors associated with VHL are very vascular (blood vessel rich) because they are driven by abnormalities in VHL.
Before starting Welireg, Korbitz had already had numerous surgeries and procedures to remove 40 tumors. Since starting the drug, he hasn’t needed any surgery.
“The idea that I may not have to have any more of those is completely life-changing,” Korbitz says. “Every time I see somebody that’s had anything to do with the development of that drug, I let them know how thankful I am.”
Korbitz’s results align with those of patients in the clinical trial.
Prior to starting Welireg, each of the 61 patients in the trial underwent, on average, about 20 tumor-reduction surgeries per year. In the two years since starting the drug, there have only been three procedures total among the 61 patients, according to clinical trial findings published in The New England Journal of Medicine.
“It’s important to note that VHL disease-associated cancers aren’t limited to the kidneys,” explains Dr. Elaine Lam, an associate professor in the department of medicine in the division of medical oncology at University of Colorado School of Medicine in Aurora. “People with this syndrome may have pancreatic tumors and tumors in their brain, spinal cord, eyes and other areas. This drug seems to be effective at shrinking down those tumors as well.” Lam is also the medical oncologist in charge of Korbitz’s care.
As time goes on, trial investigators have begun to see a slight uptick in surgeries, but the numbers are still dramatically lower than they were before the patients started Welireg.
That benefit is transformative for people living with VHL disease.
“By the time many of these patients are 30 to 40 years old, they have already had numerous surgeries,” Lam says. “This drug has made a tremendous difference in the lives of these young people who are trying to pursue careers, raise families and live their lives.”
Since VHL genes play a role in most clear cell renal cell carcinomas — and not just in people who have VHL disease — clinical trials are now underway to find out whether Welireg can get similar results in people who have metastatic renal cell carcinoma but don’t have the rare genetic disease.
That’s how 44-year-old Chris de Sa got access to the treatment.
Diagnosed with clear cell renal cell carcinoma in 2015, the Orange County, California-based attorney had a kidney removed to get rid of the cancer. But in 2016, a routine scan found a lesion on his liver, and de Sa was diagnosed with metastatic disease.
From there, he bounced from treatment to treatment. He did well on Sutent at first and stayed on it until the drug became less effective and the side effects became too much to tolerate.
Next, he enrolled in an immunotherapy clinical trial that quickly proved not to be beneficial for him.
By this point, the cancer had spread to multiple sites throughout his body. It was growing fast on his liver, and doctors suspected it was in his lungs, too. Tumors on his spine had begun to cause back pain.
“A tumor on my spine was actually hitting a nerve, and I could feel that,” de Sa recalls.
Then, in 2018, de Sa got the chance to enroll in the LITESPARK-001 trial under Jonasch’s care. In this trial, people with advanced clear cell renal cell carcinoma who do not have VHL disease and have progressed on other treatments receive Welireg alone.
Within about three months, when de Sa had his first scan to see whether the drug was working, all the tumors had begun to shrink. He is among the 1 in 4 patients in the trial who responded to the drug.
Today, after about two years on Welireg, de Sa has no more back pain from the tumor on his spine. The remaining tumors are stable, and the lesions on his lungs have all but disappeared.
“I have zero pain. I’ve been stable for the past couple of years and continue on that course. My prognosis is very, very good,” he says.
About 1 in 6 people in the trial have continued to respond to the treatment after more than three years.
When de Sa says “zero pain,” he means none related to Welireg, either. The only significant side effect he continues to have, after two years on the drug, is borderline anemia, which is common with Welireg.
Besides anemia, the other common side effects of Welireg are fatigue and hypoxia (low oxygen levels). Korbitz deals with all of them.
“Living in Denver, at a higher altitude, I get winded, and I get exhausted pretty quick,” he says.
Welireg may soon be joined on the market by other HIF-2 alpha inhibitors. Clinical trials are already underway to test other drugs in this class.
NiKang Therapeutics Inc. is currently recruiting adult patients with locally advanced or metastatic clear cell renal cell carcinoma, with and without VHL disease, for a phase 1/2 clinical trial of its as-yet-unnamed NKT2152. The trial will test the dose and efficacy of the drug as a single agent.
Novartis is also recruiting patients for a study of its own as-yet- unnamed HIF-2 alpha inhibitor, DFF332. This trial is open to adult patients with clear cell renal cell carcinoma and patients aged 12 and older with various types of malignancies that arise from VHL disease and certain other gene mutations.
Investigators will study the efficacy of the drug by itself and in combination with other drugs.
Arrowhead Pharmaceuticals has completed a phase 1 safety trial of its HIF-2 alpha-targeted drug, designed to stop overproduction of HIF-2 alpha. The study was recently published with mixed results.
Trials are also underway to test Welireg in combination with other agents. The LITESPARK-003 trial tested the efficacy of the medication in combination with the targeted drug Cabometyx (cabozantinib) in people who previously received immunotherapy for clear cell renal cell carcinoma.
Cabometyx is a kinase inhibitor that blocks several kinases involved growth signaling pathways, including vascular growth factors. Just over 30% of the patients in the trial responded to the combo. About 20% of trial participants were still responding to the treatment nearly two years later.
Ongoing LITESPARK arms will examine Welireg in combination with Keytruda (pembrolizumab) and also Lenvima (lenvatinib), another kinase inhibitor.
“It’s very exciting to have a novel approach to the treatment of these kidney cancers,” Millado says. “And it will be exciting to follow the long- term results.”
To learn more about how Welireg changed Korbitz's life, listen to this "Cancer Horizons" podcast episode.
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