Targeted therapies are defined as drugs that block critical functions specific to cancer cells, selectively disabling them and sparing normal cells. 

Hypoxia- inducible factor-2 (HIF-2) alpha inhibitors represent a new class of drugs that is transforming the lives of patients with renal cell carcinoma (RCC) and von Hippel- Lindau (VHL) disease. These drugs attack a unique signal that makes certain cancer cells grow aggressively. 

VHL disease, which typically required multiple surgeries to remove tumors, may now be managed by a therapy that shrinks tumors in sensitive areas of the body, including the kidney, brain and spine, while reducing the risk often associated with undergoing surgery.

HIF is a protein typically kept in check by the VHL protein that is produced in patients with normal VHL genes, and it serves as an oxygen sensor. But when VHL is mutated, the HIF protein is allowed to accumulate, and the cell inappropriately behaves as though it is in a low-oxygen state, setting off a cascade of processes down the line that promote the growth of abnormal blood vessels and facilitate the development of cancer.

Unfortunately, a therapy was not available to target the effects of this genetic mutation in patients with RCC until 2021, when Welireg (belzutifan), the first HIF-2 alpha inhibitor, was approved by the Food and Drug Administration for the treatment of RCC and VHL disease. This new class of drugs can also be used to treat patients with clear cell RCC without VHL disease because these tumors can still have abnormalities in the VHL protein.

Reducing tumor size is one thing, but being able to do that with tolerable side effects increases the appeal of new drug targets. Some patients treated with HIF-2 alpha inhibitors have reported manageable side effects such as borderline anemia, fatigue and other symptoms associated with a dampened response to low oxygen levels.

Discovering different genetic mutations to target for the treatment of patients with RCC, among other cancers, continues to add to the excitement of drug development in this area. As we look to the future, it will be interesting to see what else is in the pipeline that produces such a strong impact on patients both in the short and long term.

The University of Texas MD Anderson Cancer Center

For more news on cancer updates, research and education, don’t forget to 

Articles

Editor's Page

Discovering different genetic mutations to target ... continues to add to
the excitement.

Genetic Targets Open the Door to New Treatment Options in Kidney Cancer

not a sprint” is a common phrase that applies to many challenges in life, particularly to patients who’ve been diagnosed with cancer. 

Their race is a long one, riddled with ups and downs, whether it be at diagnosis, throughout treatment, after treatment or even during survivorship. A patient with kidney cancer who receives treatment with newer agents such as immunotherapy drugs and tyrosine kinase inhibitors, for example, may experience side effects as the therapy effectively reduces tumor size — and may become nervous about the possibility of their treatment dose being lowered or even stopped. However, findings from clinical trials have demonstrated that dose reductions or even stopping treatment until side effects are resolved may still result in effective treatment of the disease.

®, we spoke with two patients treated with tyrosine kinase inhibitors and immunotherapies for kidney cancer who experienced 

. These side effects included high blood pressure, an underactive thyroid and elevated liver enzymes, all of which were managed with medications. And they continued to respond to their treatments despite these challenges.

We also spoke with two other patients with renal cell carcinoma and 

 who have benefited from treatment with targeted drugs called hypoxia-inducible factor-2 alpha inhibitors, which represent a novel approach for treating these kidney cancers.

Also in this issue, an expert discusses how the treatment of sarcomatoid renal cell carcinoma has vastly changed during the past few years with the Food
and Drug Administration’s approval of immunotherapies. We also spoke with a pediatric oncologist to learn more about how the treatment of Wilms tumor has evolved the past 20 years, as part of our 20th anniversary content series.

Other topics addressed in this special issue include different surgical options for kidney cancer, what we can learn from “failed” clinical trials and the importance of becoming an active participant in one’s care.

As always, we hope you find our stories inspirational and informative. Thank you for reading.

Going through cancer is a marathon, not a sprint.

Running the Race of Cancer

Although patients with kidney cancer put their care in the hands of doctors, it truly takes a village for a patient to navigate their cancer journey, including loved ones, caregivers and other members of the cancer team. This collaborative approach may help patients digest the news they receive over time and how they respond to treatment.

As part of its “Speaking Out” video series, on behalf of KidneyCAN, 

® spoke with Meryl Uranga, a kidney cancer survivor and a patient advocate, about working as a team with clinicians, caretakers and loved ones as support throughout your cancer journey and taking a step back to process each part of diagnosis and treatment.

Q: Why is it so important for patients to be their own best advocate, especially when it comes to their care?

A: It’s a topic that I’m very passionate (about) and have a very personal connection with. The caretakers and patients that are going to be coming in on your behalf are one of many, many patients that your doctors are going to see, that your clinicians are working with. 

So you really have to take responsibility for your care, your decisions and, most of all, the empowerment of knowing what’s going on with your case. And instead of being someone who’s taking direction, you want to be in a mindset of working as a team with your clinicians. And it makes all the world of difference in terms of how your care will go going forward.

Q: How can patients make sure they’re effectively communicating with their physicians when it comes to their preference on treatment, quality of life and side effects? 

A: I think like in any situation, you have to set expectations at the beginning of the relationship. You need to, first of all, choose a clinician that is going to work with you, do the things that you’re looking for and be able to communicate the way that you want to. You want to set the expectation (of ), “I want to be an active participant. I want to know what’s going on. I want to communicate. I want to be involved in decision-making.”

If you have a caretaker that you want to be involved, you need to communicate that because there are, like in any profession, certain areas they’re not going to be a good fit. You’re going to meet doctors — and I went through a few before I found mine because we weren’t on the same page. So you have to make sure that those expectations are set and they know what kind of patient you are. 

There are a lot of people that are very comfortable just taking direction from authority figures like a doctor, (but) if you want to be in that empowerment mindset and you want to be a partner, you have to make sure that they want that as well. I really recommend finding that right fit in terms of experience, specialty areas and the communication style that they’re willing to provide and work with you on.

Q: How can a caregiver or a loved one also be a part of this patient-physician communication? 

A: Bring them with you, introduce them, let (your care team) know that you want them there, that you want them to have the information that you have, that they will be working with you on decision-making (and that) they may be taking notes. 

There are a lot of times when, unfortunately, we get not the greatest news — and it can be jarring — so you want to have somebody there with you. Again, as long as you’re all on the same page, there’ll be a tremendous working experience and relationship. 

But the thing that I would stress is to make sure that is something that they allow; for whatever reason, they may not do that in their practice. So you have to get that set up — those expectations set and agreed to upfront.

Q: Looking back on your own experience, what is your biggest piece of advice for others when it comes to patient-physician communication?

A: My biggest piece of advice is born from my own experience. When
I was diagnosed, I was in a fog. I am normally a very proactive, research-oriented person. But when you get this 

kind of news, it’s very difficult to pick yourself up and get in that mindset right away. And so you kind of go through the motions. 

My only regret and what advice I give to someone newly diagnosed is: Don’t make too many decisions until you can get your feet under you. I personally made some decisions looking back that I would not have done six months later when I got more educated and more involved in learning about what was going on.

So take a breath. Whatever is going on with you, it has been going on for some time, especially with kidney cancer because almost everyone I know — and there’s a lot of people that I know that have been diagnosed with this disease — has said that their physicians have said that they’ve had it for many, many years. It’s a very silent, quiet- growing (disease) for a while with no symptoms, no signs. You got a few more weeks, so chill. A lot of people just panic, like, “Get this thing out of me,” or “Start my treatment.” But become educated. It’s hard because you’ve got that emotional jarring (feeling), your world’s upside down, and so you have to take a breath, get some land legs and then start understanding what the next best steps are.

And if I had to do it all over again, which obviously I can’t, that’s what I would have done. What I was doing was just taking direction and advice from the people that haphazardly diagnosed me. In my case, I think it worked out OK, but within six months and recovering from two major surgeries, I was able to really understand where I needed to be for care and make those changes. Had I done that pre-surgery, I have no way of knowing if it would have been a better outcome, a different outcome. I have no way of knowing, but I highly encourage people to take that time.

Speaking Out

As a part of its “Speaking Out” video series, CURE® spoke with Meryl Uranga, on behalf of KidneyCAN, about the importance of working as a team with their clinicians and getting educated before making decisions.

Becoming an Active Participant in Kidney Cancer Care

The news often highlights positive clinical trials, in which the outcomes that researchers were hoping for occur, potentially leading to Food and Drug Administration (FDA) approvals. But what happens with trials that miss the mark?

One expert said those “misses” should not be considered a loss altogether, but rather, something that is to be expected and does not mean the end of the road for a particular therapy.

“We have to accept that reality,” Dr. Nizar M. Tannir, professor in the department of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “Most trials are going to fail, but a silver lining is ... there will be lessons learned from a trial that failed. What went wrong? Was the drug not potent enough? ... Maybe we can repurpose a drug or use a drug in a different patient population.”

Tannir and colleagues are facing exactly that after the CANTATA clinical trial. Results from the trial were presented at a major oncology conference earlier this year and published in 

In the trial, 444 patients with metastatic clear cell renal cell carcinoma (RCC) were randomly assigned to Cabometyx (cabozantinib) with the glutaminase inhibitor telaglenastat or placebo. No significant difference was seen between the two groups for progression-free survival (the time during and after treatment that a patient lives with the disease without worsening), despite the treatment being well tolerated.

“That was disappointing for me and many of the investigators in the field who participated in the trial and for many people who were hopeful that maybe we will have a new class of agents, a new target for RCC, which is the glutamine pathway and tumor metabolism,” Tannir said. “But as we know, many, many trials fail — many trials with promising, encouraging data in earlier-phase trials.”

Tannir explained the reasoning behind inhibiting the enzyme glutaminase to treat patients with metastatic RCC.

“Many solid tumors including RCC had increased glutaminase expression when we tested tumor tissues,” he said. “The rationale behind that is the tumor cell relies on (certain) pathways for producing energy. A normal cell will produce energy for its survival via 

glucose (sugar), whereas a cancer cell has a faulty glucose utilization or metabolism, so tumor cells rely more and more on other pathways for survival. One of those pathways is (the amino acid) glutamine.”

Because the rationale is there, further research may continue in this area.

“(Results from CANTATA don’t) mean that the idea of targeting tumor metabolism or glutamine should be dead,” Tannir said. “When you give a treatment, everybody with kidney cancer, even if they all had clear cell (RCC), all of these RCCs are driven differently. You need to see if your drug is going to work. It might work for 10% of the patients, 15% or 20%. We need to identify who are (the) patients who (will benefit most).”

Tannir gave an example of another target with negative trials before it was approved by the FDA — anti-CTLA-4 therapies, which are immune checkpoint inhibitors. The first trial assessing an anti-CTLA-4 therapy was conducted more than 15 years ago in patients with RCC. In this phase 2 trial, patients were treated with a 3-milligram-per-kilogram dose of Yervoy (ipilimumab) and had a 13% objective response rate (a measurable response) to the therapy. 

However, the dose was deemed too toxic for patients, leading to other studies with other doses. Yervoy was ultimately approved in combination with Opdivo (nivolumab) for RCC, among other indications.

It is important for patients to know how participation in clinical trials is valuable to further the space along.

“Patients need to participate in trials, we need to design and conduct trials, we need to develop new drugs, we need to test new drugs, and I hope patients will see the benefit of this,” Tannir said. “We appreciate the trust of patients and families to support (this). It’s not easy to participate in clinical trials. There is demand on patients and their caregivers — time, effort, transportation, finances, all this to enroll on a clinical trial.”

Tannir added that persistence is also necessary to further the field and develop additional treatment options.

“Do not despair, do not give up and do not be discouraged that the trial was negative,” Tannir said. “There will be other (trials) that will be positive. We just have to keep pushing the envelope; I am confident that in the near future we will make cancer history.”

For more news on cancer updates, research and education, don’t forget to

One expert explains how the road to cancer drug development isn’t a smooth one, but progress can be made nonetheless.

The Silver Lining of Failure in Cancer Drug Development

Advancements in the treatment of sarcomatoid renal cell carcinoma (RCC) have given patients more options, particularly those with metastatic or recurrent disease whose options were limited.

Approximately 10% of patients with RCC have a form of the disease with sarcomatoid features, such as cells shaped like ovals or spindles, said Dr. Mohit Gupta, a urologic oncologist and the director of clinical research for the department of urology at MedStar Georgetown University Hospital in Washington, D.C.

“Essentially (sarcomatoid cells look different) under the microscope,” Gupta explained. “What that means for the patient is that (it) is actually an aggressive type of cancer. ... Patients who have these types of features often present at very advanced stages or with what’s called metastatic disease, basically cancer that has spread to other parts of the body outside the kidney itself.”

Gupta noted that approximately 15% of patients who first present to a urologist with sarcomatoid RCC are diagnosed with stage 4 cancer. He emphasized the importance of reporting symptoms to oncologists, especially upon diagnosis of RCC, because bone pain and changes in mental status may indicate that the disease has spread to other areas of the body, most commonly the lungs, liver, bone or brain.

If RCC has not spread, surgeons should aim to remove the cancer either with a partial nephrectomy (removal of part of a kidney) or a bilateral nephrectomy (removal of both kidneys).

“The most important thing, just like for any kidney cancer, is that 100% of the tumor is removed and that when the pathology doctors look under the microscope, they have something called nega- tive margins, which means 100% of the cancer was removed,” Gupta said.

If the pathology report indicates that the RCC has sarcomatoid features, the patient may be treated with immunotherapy. Keytruda (pembrolizumab) was approved by the Food and Drug Administration (FDA) in November 2021 for the treatment of patients with RCC, including patients with sarcomatoid RCC.

In the KEYNOTE-564 clinical trial that supported this FDA approval, patients with RCC, including those with RCC with sarcomatoid features, underwent nephrectomy and received once-weekly treatment with Keytruda every three weeks for one year. Treatment reduced the risk for disease recurrence by nearly 30%.

“What was most interesting was that for the patients who had sarcomatoid features on their pathology, this medication did even better,” Gupta said. “It actually helped those patients even more compared (with) patients who didn’t have sarcomatoid features. So there is luckily a treatment option in case a patient goes through surgery and they have this on their final pathology.”

Gupta noted that before this FDA approval, there wasn’t much in terms of treatment for patients with sarcomatoid RCC.

“We just prayed and hoped that the cancer didn’t come back,” he said. “There wasn’t much that we could do. And the problem was when (the cancer) did come back, we also had very limited options.”

Patients with metastatic sarcomatoid RCC or those with recurrent disease now have more treatment options thanks to immunotherapy. Metastatic or recurrent sarcomatoid RCC was previously treated with chemotherapies and vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs), but these treatments had minimal effect on disease with sarcomatoid features. Now, however, patients with sarcomatoid RCC often respond well to the immunotherapy combination of Yervoy (ipilimumab) and Opdivo (nivolumab). Compared with VEGF-TKIs, Opdivo plus Yervoy significantly improves overall survival and progression-free survival in patients with sarcomatoid RCC.

“What we have found is that this immunotherapy works extremely well for these types of patients,” Gupta said. “That has really been a game changer for us, both for patients with metastatic cancer upfront and for patients whose cancer has come back.”

Even with all the progress made in treating patients with sarcomatoid RCC, not everyone responds to the current immunotherapy options, so more research is needed to find treatments to help these patients.

More research is also needed to determine how to best manage patients with metastatic disease. Gupta mentioned that before immunotherapy, patients with metastatic sarcomatoid RCC were treated with cytoreductive nephrectomy, which is a surgery to remove as many cancer cells as possible and may include surrounding organs.


Now researchers are wondering whether it might be beneficial to administer immunotherapy before potential surgery.

“For patients who have that sarcomatoid-type kidney cancer, because the immunotherapy works so well, what we’re doing now is giving them immunotherapy upfront because what we’re seeing is that if we operate on them first, oftentimes the cancer comes right back or it grows even faster while the patient is recovering from surgery,” Gupta said. “Instead of doing that, we are basically giving ... immunotherapy upfront for the patients that respond and are still healthy. And basically, all their other sites of disease shrink to just the kidney mass itself, (and then we) operate on them. But if (they don’t respond to therapy) or the cancer continues to grow, then we also spared patients from an unnecessary surgery.”

FDA-approved immunotherapies offer patients with metastatic or recurrent sarcomatoid RCC more treatment choices and improved outcomes. 

Sarcomatoid Renal Cell Carcinoma: From Limited Options to a 'Game Changer'

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 

, 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.”

Clear Cell and Renal Cell Carcinoma and the VHL Gene 

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.

Welireg Receives FDA Approval in VHL Disease 

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.”

Welireg Made a von Hippel-Lindau Survivor Feel Like a 'Medical Miracle'

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 

“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.”

HIF-2 Alpha Inhibitors May Help Patients Without VHL Disease 

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

Feature

HIF-2 alpha inhibitors are transforming therapy for patients with renal cell carcinoma and von Hippel-Lindau disease.

A Sea Change in Treatment for von Hippel-Lindau Disease

When Marissa Willis began feeling pain on her left side in May 2013, she initially thought she might have pulled a muscle during one of her workouts. 

At 38, the mother of two was in good health and exercised regularly. Yet when the pain persisted, Willis headed to her local urgent care center and was shocked when X-rays revealed a mass on her left kidney.

“I saw my primary care provider the next day for a sonogram, and the next two weeks were a whirlwind of appointments, scans and tests at the University of Kansas Medical Center,” says Willis, who lives in Blue Springs, Missouri. “Ten days later, I had a radical left nephrectomy to remove both the tumor and my left kidney.”

After her surgery, Willis was doing well until a follow-up imaging test 10 months later found a small spot on her lung.

“Since the spot was less than a centimeter, my oncologist decided it was reasonable to watch the mass and see if would grow,” Willis says.

Three years later, in 2017, an imaging test determined another spot on her lung was large enough to biopsy. Test results found the cancer had metastasized to her lung, and Willis began four cycles of high-dose interleukin-2, a form of immune-stimulation therapy.

It wasn’t until Willis was prescribed her current drug regimen of 

Votrient (pazopanib), a tyrosine kinase inhibitor

 that targets cancer-supporting blood vessels, that she began to experience side effects from her cancer treatment.

“I had never had high blood pressure before, but after being on Votrient for a short time, I was diagnosed with both hypertension and an underactive thyroid,” Willis says.

Although tyrosine kinase inhibitors and checkpoint inhibitors have proven to be extremely effective in treating patients with renal cell carcinoma, they also carry the possibility of side effects, which can be worrisome for patients.

In Willis’ case, her care team had discussed potential side effects with her in advance and monitored her bloodwork and blood pressure levels so that any changes with her health could be immediately addressed.

“My doctor put me on medication to lower my blood pressure and treat my underactive thyroid. I monitor my blood pressure daily and have my thyroid-stimulating hormones levels checked on a regular basis,” Willis says. “While I will be on both medications indefinitely, I’m happy to be living a pretty normal life.”

Because treatments for kidney cancer, including immunotherapies and tyrosine kinase inhibitors, carry the risk of side effects, it’s important for patients and their oncology care team to weigh the risks versus the benefits of each treatment, according to Dr. Thomas Hutson, director of the urologic oncology program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center in Dallas and a professor of medicine at Texas A&M University School of Medicine in Bryan.

“Immunotherapies and (tyrosine kinase inhibitors) have shown success in treating metastatic cases by shrinking tumors and offering many patients remission and long-term survival,” Hutson explains. “Many of the common side effects tend to be fatigue, skin rashes and chronic muscle-related issues such as cramping or joint pain.”

Findings from a study published in the medical journal 

 in 2021 showed that approximately 40% of patients taking checkpoint drugs as immunotherapy develop acute and chronic complications such gastrointestinal side effects, rash, arthritis or endocrine dysfunction.

If a patient encounters more severe side effects, Hutson says doctors will look at adjusting or lowering the dose of the medication, making the side effects manageable.

“Some patients are reluctant to lower their medication dose, mistakenly believing it will also lower the effectiveness of the medication,” Hutson says. “This isn’t the case, and when prescribing treatments, doctors take (into) consideration a patient’s quality of life. If the medications are taking too much of a toll on a patient and adversely affecting their health, a decision will be made about stopping the medication, since we don’t want to continue a high-dose drug regimen that will cause patients to suffer unnecessarily.”

Hutson tells patients their cancer journey is “a marathon, not a sprint,” and if they need to stop an immunotherapy or tyrosine kinase inhibitor drug — at least temporarily — they can later resume treatment on a lower dose or sometimes even a different drug. 

patients should always report side effects

“Reducing dosages isn’t bad,” Hutson says. “In clinical trials, dose reductions are quite common, so we always tell patients the medication dose they start at may not be the same dose they stay on. In fact, two-thirds of all (patients with cancer) need to be switched to a lower dose. We strive to balance the side effects with safety and quality of life.” 

Information from clinical trials shows that the rates of response and length of time to when there may be progression of a tumor do not seem to differ among patients who need a dose reduction due to side effects compared to those who may not.

In rare cases, Hutson notes that immunotherapy drugs, especially when combined, can trigger a more severe autoimmune response causing inflammation of the lungs, liver or colon. 

This was the case for Chase Griffith, 45, of Dallas, who was diagnosed with kidney cancer in December 2018. After Griffith underwent a complete nephrectomy, his follow-up scans showed no sign of cancer — until April 2021, when an MRI and CT scan found that the cancer had metastasized to Griffith’s liver.

After meeting with doctors at The University of Texas MD Anderson Cancer Center in Houston and UT Southwestern Medical Center in Dallas, Griffith decided his best course of action was to begin a triple-medicine clinical trial using two immunotherapy drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), combined with the tyrosine kinase inhibitor Cabometyx (cabozantinib). 

The phase 3 clinical trial is comparing treatment with Yervoy and Opdivo followed by Opdivo alone to treatment with Yervoy and Opdivo followed by Opdivo with Cabometyx in patients with untreated renal cell carcinoma that has spread to other parts of the body. 

Researchers hope to determine if the addition of Cabometyx to the usual treatment will make the therapy more effective at stopping the growth of tumor cells.

“When I went in to get my third dose of the treatment regimen, I had bloodwork done and my oncologist found that (my) liver enzymes were off the charts,” Griffith recalls. “Basically, the immunotherapy caused my immune system to attack my healthy liver tissue.”

Doctors told Griffith they would immediately stop the therapy and begin a course of steroids to suppress the immune response. Because Griffith had been cautioned ahead of time about potential side effects, he wasn’t surprised and believed he was in good hands with his oncology team.

“I was put on 200 milligrams a day of prednisone that I took for several months before doctors began tapering me off the medication,” Griffith says. “I got down to 10 milligrams in February of this year and started having the same side effects, including insomnia and an elevated heart rate. After going to an urgent care center, I learned that my liver enzymes were even higher than before.”

Griffith was hospitalized and given both prednisone and the high-level immunosuppressant CellCept (mycophenolic mofetil), which is often prescribed to prevent organ rejection after transplantation. He remained on the drugs for several months.

Because he has chromophobe renal cell carcinoma, a rare form of kidney cancer, Griffith knows his doctors are using novel approaches to create targeted therapies that stop or slow the growth of his cancer.

“This past February, doctors started me on another (tyrosine kinase inhibitor), lenvatinib (Lenvima), and an mTOR (inhibitor) therapy, everolimus, that have resulted in a 20% shrinkage in my tumor,” Griffith says. “Today, I feel good, and my doctor says I have no new tumors and that my existing tumors have stabilized.”

Frequent Communicatoin Is Key to Managing Side Effects 

According to Laura Wood, an oncology nurse and former renal cancer center research coordinator at Cleveland Clinic Taussig Cancer Center, high blood pressure, or hypertension, can be a side effect of some of the multikinase inhibitors used to treat kidney cancer since they act by affecting the blood vessels in tumors and can also have effects on normal blood vessels that regulate blood pressure. 

These drugs include Sutent (sunitinib malate), Lenvima and Inlyta (axitinib). In addition, Wood notes that a class of drugs known as mTOR inhibitors, including everolimus, rapamycin (sirolimus) and temsirolimus (CCI-779), can often cause side effects such as elevated blood sugar, cholesterol and triglycerides.

“We tell patients in advance they shouldn’t be surprised if they develop any of these conditions while undergoing cancer treat- ment,” Wood says. “They’re very manageable conditions, and (the patient’s) bloodwork and symptoms improve after adjustments are made to their cancer treatment and medications are given to treat the side effects. Some side effects may result in long-term symptoms which require ongoing discussions with your oncology team or other specialists to manage.”

Wood says it’s crucial for health care providers to provide patients with kidney cancer with early and ongoing education regarding potential side effects and for patients to report these as soon as possible to obtain relief and avoid any organ damage or other long-term problems.

Reporting side effects can also help researchers better understand side effects and develop additional strategies on how to best manage them. 

In 2017, the Severe Immunotherapy Complications Service was launched at Massachusetts General Hospital in Boston to treat and study patients with immune complications from immune checkpoint inhibitors. Many other cancer centers have similar programs and multidisciplinary teams to manage immune-related side effects.

Dr. Naomi B. Haas, an oncolo- gist and director of the prostate and kidney cancer program at Penn Medicine and a professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, notes that in rare cases, side effects might even be considered something of a positive.

Haas cites an analysis of clinical trials conducted at Dana-Farber Cancer Institute in Boston showing that patients with advanced kidney cancer who were diagnosed with high blood pressure and prescribed medications called angiotensin system inhibitors, including angiotensin-converting enzyme inhibitors and angiotensin system blockers, lived longer and had better outcomes than patients who weren’t diagnosed with hypertension and treated with those medications.

Even when patients experience milder side effects, Haas says they should discuss changes with their oncology team. 

The Kidney Cancer Association offers a printable side effect tracker on its website, www.kidneycancer.org, to make it easier for patients to track their symptoms and inform their oncology team about symptom severity and how often symptoms are occurring.

“In some cases, patients can lose their sense of taste and say their food tastes like cardboard,” Haas says. “As a result, they aren’t going to eat as much and will ultimately lose weight, which we don’t want.”

To address this, Haas says oncologists will typically ask a patient to cease taking their medication for a few days to determine whether it’s the drug or the disease that’s causing the problem. If it’s the medication, Haas notes that drugs such as mirtazapine can be prescribed to help stimulate a patient’s appetite.

Diarrhea is another common side effect that Haas says can impact both a patient’s physical and emotional health. Haas says patients should never be embarrassed to discuss any changes in their health with their oncology team.

“We don’t want patients to be miserable or afraid to venture out socially because they’re experiencing diarrhea,” Haas says. “We can prescribe probiotics and advise changes to their diet to remedy their situation. In severe cases, we might begin steroid therapy.”

In cases of renal cell carcinoma, although side effects can initially seem scary, Haas says most are treatable and are outweighed by the benefits patients receive from tyrosine kinase inhibitors and checkpoint inhibitors.

Newer drugs for kidney cancer have proven extremely effective but can cause unwanted symptoms that affect safety and quality of life.

Kidney Cancer Special Issue 2022 | CURE