Sonya Collins

After a rectal cancer diagnosis, Sarah Rack avoided surgery through a clinical trial at MD Anderson, where immunotherapy eliminated her tumor, preserving her rectum. Image Credit: Rachael Boer.

When Sarah Rack talks about her diagnosis of rectal adenocarcinoma on Election Day 2020, she does not mince words.

It was the fear of illness and death, concern for her children — one a college sophomore at the time and the other still in high school — and the threat of surgical removal of her rectum and living the rest of her life with a colostomy, the surgical connection of the colon to an abdominal opening that lets stool be collected in a bag outside the body.

"Now, I'd be able to handle it better, but at the time, I said I'd rather be dead than have a colostomy. I was so depressed," says the 58-year-old psychiatrist who lives in Memphis, Tennessee.

But Rack was offered a possible escape from that fate: a spot in a clinical trial that would test whether treatment with medication alone could eliminate the need for surgery in people with tumors that had specific genes that suggested they would respond well to the medication.

Surgical removal of the affected organ was once a foregone conclusion in many cancers, including certain cancers of the rectum, colon, stomach, bladder and uterus. These life-altering surgeries may have consequences for digestion, excretion, fertility, sexual function and countless other aspects of daily life. But now, an increasing number of people with some of these cancers have a choice: surgical removal of the organ or systemic therapy and added surveillance.

“Depending on the organs involved and what the surgical pathway would have looked like, surgical resection can greatly reduce your quality of life,” says Dr. Kaysia Ludford, an assistant professor in the Department of General Oncology at The University of Texas MD Anderson Cancer Center in Houston. “An organ-sparing approach is paradigm-shifting.” 

Although the removal of an organ often offers the greatest chance of a cure in cancers such as rectal and bladder, these surgeries come at a cost. For some people, rectal resection can mean living with a permanent colostomy along with other potential collateral effects. “Even with a minimally invasive approach, we can affect sexual function, bladder function and fertility,” says Dr. Fergal Fleming, a colorectal surgeon at the University of Rochester Medical Center in New York.

The same is true of bladder removal, a procedure called radical cystectomy, for bladder cancer. The procedure not only takes the bladder but also part of the small intestine, which is used to create a “neobladder,” a pouch to hold urine. Nearby organs and tissue are also removed, which can affect fertility and sexual function.

"It’s fraught with complications," says Dr. Roger Li, a genitourinary oncologist at Moffitt Cancer Center in Tampa, Florida, "because it’s one of the most complex surgeries we do in urology, and it’s oftentimes done in a patient population who is not at their healthiest."

Saving Organs in Cancers With Specific Genes

Rack got into a clinical trial at MD Anderson that tested whether treatment with the immune checkpoint inhibitor Keytruda (pembrolizumab) before surgery might eliminate the need for surgery in people whose tumors had cells with mutations in genes that correct DNA errors, a condition known as mismatch repair deficiency.

Twenty-seven of the 35 trial participants, including Rack, had colon or rectal adenocarcinoma. The remaining eight had adenocarcinoma of the stomach, pancreas, duodenum (an upper part of the small intestine), ampulla (a small opening that enters the duodenum) or uterus. One patient had a type of brain tumor called a meningioma.

They received Keytruda every three weeks for six months. At the six-month mark, they could have surgery or continue the medication for a year, followed by observation.

Eighteen participants chose the nonsurgical option of Keytruda, 10 of whom completed the full year. After three years of follow-up, 14 of the 18 patients were alive with an intact organ. Two patients were lost to follow-up. One patient died of unrelated causes. Another died from disease progression. Although the majority of those in the study and the majority who benefitted from treatment had colorectal cancer, one patient who took the nonsurgical option had gastric cancer and is still in remission now, nearly four years later.

“The patient still has the organ intact and didn’t require the stomach to be resected,” says Ludford, who co-led the study. “As you can imagine, certain organs have serious implications for quality of life if they have to be resected, [such as] the stomach, for instance, so we want to explore the possibility of sparing those organs, and that’s what led to this study.”

The results were published in 2023 in the 

. In a similar study, 14 people with locally advanced rectal cancer with mismatch repair deficiency had a complete clinical response to the immunotherapy drug Jemperli (dostarlimab), which works in the same way as Keytruda, eliminating the need for surgery.

Rectal tumors do not have to carry the mismatch repair deficiency mutation to be eligible for a nonsurgical approach. The treatment plan for many rectal cancers used to be what is called “sandwich therapy,” Fleming says. “You got a little bit of radiation and a very small dose of chemo, which we call a sensitizing dose; then you’d have surgery and then three to six months of chemo afterwards.” But now researchers are testing the effects of front-loading the treatment plan with all the systemic therapies and radiation and then reassessing to see whether the patient still needs surgery.

Not too long ago, Fleming says, “Chemoradiation [for rectal cancer] without surgery would have been considered heresy.” Now, he adds: “Sometimes very well-read, motivated patients say they don’t want surgery, and also, we started seeing very good responses to systemic therapy. It wasn’t actually the primary end point of some of these studies, but they started realizing patients had a complete response.”

The approach is showing promise in many other cancers as well. Published research has explored the effects of organ-sparing approaches in cancers of the throat, vagina, sinus cavity and bladder.

Organ-sparing treatment for bladder cancer has allowed 65-year-old Darrell Murray of Orlando, Florida, to keep his bladder intact since his cancer diagnosis in 2016 and, for the most part, carry on with life as usual.

Murray had non-muscle invasive bladder cancer, an early-stage cancer restricted to the lining of the bladder. He got the standard therapy — 21 rounds of bacillus Calmette-Guerin (BCG), a combination therapy that includes a cancer vaccine and immunotherapy. Afterward, he was cancer-free until a recurrence in 2020.

The thinking in bladder cancer has typically been that if it recurs after BCG, there is a higher risk for it to spread into the muscle wall of the bladder, becoming what is called muscle invasive and eventually metastasizing. “There has traditionally been this aggressive approach that once you develop recurrence, it’s an indication for us to perform radical cystectomy to remove the bladder and reconstruct the urinary tract,” Li says.

Since 2020, Murray has had four recurrences. “Every physician, every time,” Murray says, “would bring up cystectomy as an option. I realize that’s the gold standard, but I had to ask myself what life would look like with a cystectomy.”

“They would take the bladder, prostate, lymph nodes and about 18 inches of your intestine to create a vessel for urine,” Murray says. “But the intestines are designed to absorb nutrients, not store urine. You’d absorb waste products from your kidney in the neobladder. There’s mucus buildup and sometimes blockages, so you have to catheterize yourself.”

Increasingly, people like Murray with recurrences of non-muscle invasive bladder cancer are being offered alternatives to surgery. At every turn, Murray has chosen to keep his bladder and receive the next available medication. He reasons that even after radical cystectomy, there is no guarantee a recurrence will not happen.

After Murray’s first recurrence, he had six rounds of Keytruda; after another recurrence, he had eight rounds of chemotherapy; on the third recurrence, he had BCG plus interferon, which helps the body’s immune system fight diseases.

Finally, at the fourth recurrence, Murray was almost ready to give in and have his bladder removed when he was offered a spot in the BOND-003 trial led by Li at Moffitt Cancer Center. In this trial, people with non-muscle invasive cancer that did not respond to BCG received 21 treatments with the oncolytic, or tumor-destroying, virus cretostimogene grenadenorepvec (CG0070), designed to replicate inside cancer cells and kill them. It also releases a protein that helps the immune system kill cancer cells.

Murray was among the more than 75% of trial participants who had a complete response to the treatment. The Food and Drug Administration has granted the experimental drug both fast-track and breakthrough therapy designations to speed its path to approval. Research is underway to test the same approach in muscle invasive bladder cancer.

Murray is once again cancer-free. He has been for over two years.

Although he has no regrets about keeping his bladder intact, the treatments he has endured over the past eight years have been no picnic, he says. Bladder cancer medications are intravesical, which means they go directly into the bladder, and the patient must hold them in, resisting an intense urge to urinate, for a half-hour or more. “I kind of liken it to battery acid, Coca-Cola and a package of Mentos,” Murray says of the sensation. “It was really tough sometimes.” The more treatments he underwent, the harder it was.

Is Organ-Sparing Treatment Right for You?

Each time Murray faced a recurrence, he carefully weighed the surgical versus nonsurgical approach. “I wouldn’t say it was a no-brainer,” he says.

People who have the option of organ-sparing cancer treatment should consider several issues. First, they should understand their individual risk of recurrence and whether a recurrence might be more aggressive.

They should compare the options. When comparing the removal of a vital organ and treatment with medication, organ removal typically requires a longer recovery and significant adjustment to a new life without the organ. Still, those facing this choice should ensure that they can tolerate the intense medication therapy they would receive instead of organ removal. That includes possible side effects from medication and downtime after treatment days.

Patients should also understand what kind of follow-up will be needed in the coming months and years. A nonsurgical approach usually requires more follow-up, imaging and testing than would be required of someone who had the organ removed. This is to ensure the cancer has not come back and to catch it early if it has.

The treatment and intense follow-up often require travel to a large cancer center. “Individuals need to have access to the medical facility where they can continue this very close monitoring,” Ludford said. Transportation, additional time, added costs, time away from work and child care or eldercare may all figure into this increased monitoring.

Finally, organ-sparing treatment might be best suited to people who are less prone to anxiety. All those follow-up tests can be a source of great anxiety.

“This is something we chat with our patients about,” Fleming says. “How do you cope with uncertainty? Some people can just shut the door on uncertainty while others just can’t stop looking at the issue.” Most patients in Fleming’s practice who choose to watch and wait, even if they have a recurrence, are happy with their decision, he says.

Rack, the psychiatrist in Memphis who had rectal cancer, traveled to MD Anderson in Houston for Keytruda infusions every three weeks for 18 months. After finishing treatment, she went back to Houston for scans and labs every three months for about a year. Now, she goes every six months.

Today, cancer-free, she says she actually enjoyed the trips to the cancer center in Texas. “The treatment down there was great, and then I’d come back to work and put it out of mind,” she says.

As for whether Rack regrets holding onto the organ where her cancer scare began, there is no question she made the right choice, she says. “This is one of the happiest times in all my life.”

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Articles

Organ-sparing treatments are emerging as viable alternatives to traditional surgical interventions for certain cancers, offering patients the possibility of maintaining organ function and quality of life. Clinical trials, such as those involving immune checkpoint inhibitors like Keytruda, have shown promising results in patients with specific genetic mutations, allowing some to avoid surgery altogether. This approach requires careful consideration of individual risk factors, potential side effects, and the need for ongoing surveillance. Patients must weigh the benefits of preserving organs against the demands of intensive treatment and follow-up.

Avoiding surgery for rectal cancer, Sarah Rack of Memphis traveled to Houston for treatment every three weeks for 18 months. 

Organ-Sparing Treatments Bring New Life After Cancer

Former triathlete Lee Keenan has been treated for gastrointestinal stromal tumors (GIST) with Qinlock for more than a year.

On a summer Sunday in 2011, Lee Keenan competed in the Pleasant Prairie Triathlon in Wisconsin. At 42 years old and having completed numerous triathlons, he was in fighting shape. This time around, he decided not to focus on speed and instead just to have a good time. And that he did.

Back at home that afternoon, just over the state line in Illinois, he had energy left to man the grill at a cookout.

“It was a great day. I enjoyed the race and had a lot of fun,” says Keenan, now 54.

But Monday morning, he woke up with such intense abdominal pain that he thought he had torn something in the race. Over the next couple of hours, the pain only got worse. He got in to see his doctor that day. After an ultrasound, the doctor sent Keenan to the hospital for a CT scan. That was when they found a mass.

Doctors took a biopsy, told Keenan it was benign and scheduled a surgery to take it out. As he lay in the hospital recovering from the removal of the mass, an oncologist came into the room and introduced himself.

“At this point in my life, I didn’t even know what an oncologist was. My wife and I looked up the word ‘oncologist’ on our phones. When he came back into the room, I asked him, ‘Do I have cancer?’”

He did. Keenan had a gastrointestinal stromal tumor, or GIST, but the doctor explained that his prognosis was great. This cancer typically did not metastasize. Keenan would take medication, go in for annual scans to ensure the cancer hadn’t returned and live a long life, the doctor told him.

The next three years on Gleevec (imatinib), the treatment doctors typically prescribe first for GIST, were uneventful, Keenan says. He had no side effects from the drug and his routine scans were clear – until a scan revealed a new tumor.

After another surgery to remove the tumor, he remained on Gleevec for a few more years, until he had to have another tumor removed. Keenan’s doctor, Dr. Mark Agulnik, section chief of sarcoma medical oncology at City of Hope in Duarte, California, then put him on Sutent (sunitinib), which he remained on until a new growth required another procedure. From there, he qualified for a clinical trial that compared Ayvakit (avapritinib) to Stivarga (regorafenib). He started on Stivarga then moved on to Ayvakit. After progressing on Ayvakit, Keenan started taking Qinlock (ripretinib).

“A lot of the medicines I’ve taken weren’t even available when I first got GIST. The last three didn’t even exist at that time,” Keenan says.

The many options that have been available to Keenan reflect the dramatic advances that have taken place in GIST treatment over the last decade. This progress has been possible, in large part, because the role that driver mutations play in GIST is among the most well understood of solid tumors and one of the first that was amenable to a dramatic anti-cancer treatment effect from drugs designed to specifically target the mutations.

Over the last 10 years, five options have been added to the treatment arsenal, including new drugs and additional indications for existing drugs. This decade of progress culminated with two new drug approvals in 2020. Qinlock earned approval from the Food and Drug Administration (FDA) for inoperable or metastatic GIST after progression on the three existing GIST drugs Gleevec, Sutent and Stivarga. Ayvakit also got the nod from the FDA, which made it the first therapy for patients with the multidrug-resistant PDGFRA D842 mutation.

“Each additional option we have for treatment of these cancers adds time that we are able to control the growth and spread of these tumors, which buys people more time,” says Dr. Andrew Brohl, a medical oncologist who treats patients with GIST at Moffitt Cancer Center in Tampa, Florida.

Tyrosine Kinases — the Key to GIST Treatment 

Targeting tyrosine kinase has long been the approach to treating GIST. First-line therapies Gleevec, Sutent and Stivarga are kinase inhibitors.

Tyrosine kinases are chemical messengers that control how cells grow and divide. Doctors often liken them to an on-off switch for the process of cell growth and division. When they are on, the cell divides and produces another cell.

“Normally, in GIST, the kinase is mutated. That is, it’s always turned on,” says Dr. Margaret von Mehren, chief of sarcoma medical oncology at Fox Chase Cancer Center in Philadelphia and an investigator on the INVICTUS trial, which led to FDA approval of Qinlock.

A metabolite called ATP (adenosine triphosphate) flips the switch on by attaching — or “binding” — to the kinase. The three kinase inhibitors for GIST bind to the kinase where ATP is supposed to latch on. In effect, the drug molecules take ATP’s spot and prevent it from flipping the switch on.

Doctors typically start patients on Gleevec, switch them to Sutent if needed and then Stivarga.

These first- through third-line kinase inhibitors work for a time, but eventually cancer cells come up with a way to outsmart them.

“Once people progress on Gleevec, Sutent or Stivarga, we find they have developed additional, secondary mutations that alter the structure of the kinase and prevent these other drugs from binding,” von Mehren says.

These secondary mutations – that is, new mutations that develop in the tumor as it becomes resistant to a drug – are typically in the KIT or PDGFRA genes located on what’s called the activation loop of the kinase. Simply put, the activation loop allows the kinase to put itself in the on position.

Qinlock and Ayvakit have a different structure that allow the drug to target the altered kinases encoded by gene mutations that make the tumors resistant to first-line drugs. By acting on the activation loop, these drugs prevent the cancer-promoting kinases from getting into the position that would allow the kinase to switch to on.

Qinlock Targets Two Common Resistance Mutations 

Qinlock targets both KIT and PDGFRA mutations. Based on the results of the INVICTUS trial, the drug earned FDA approval for people who had progressed on three or more prior kinase inhibitors.

In the trial, the drug extended progression-free survival (the time during and after treatment when a patient lives with the disease without worsening) by a median 6.3 months compared with one month on placebo. The overall response rate (the percentage of patients with a partial or complete response to treatment) was 9% and overall survival (the time from treatment until death of any cause) was just over 15 months compared with about six months in the placebo group.

“Ripretinib is a very good drug for many types of GIST tumors as it affects a broad spectrum of mutations,” von Mehren says.

Qinlock seems able to block some mutations that other drugs do not: KIT mutations in two distinct locations on the gene – exons 17 and 18.

After progressing on numerous other drugs, Keenan has been taking Qinlock for almost 16 months. “I feel very lucky,” Keenan says. “It’s been effective at reducing the size of the growths. It’s been very good.”

He’s scheduled for another scan in June to ensure that the drug continues to do its job. In the meantime, the former triathlete continues to live an active life. “Like a lot of people in my group of friends, I put the running shoes away around age 47 and biking is now my main way to exercise.”

While Keenan has always had another drug to move on to, for one particular group of patients, no drug seemed to work.

“A primary PDGFRA mutation known as D842V was resistant to all the drugs from the get-go,” says Dr. Michael Heinrich, a professor of medicine at Oregon Health & Science University Knight Cancer Institute in Portland. “We tried different things but none of them ever worked, so we had to go back to the test tube.”

In the development of Ayvakit, intended to be a KIT inhibitor, researchers learned that it seemed to block this less common mutation as well. Expanding the search for trial participants to sites around the world, the NAVIGATOR trial, which included Heinrich as an investigator, began to enroll patients with the D842V mutation.

In the clinical trial, most patients with a PDGFRA mutation on exon 18 responded to the drug. The highest response rate was among people with a D842V mutation.

Shortly after 53-year-old Brian Gilhooly received a diagnosis of GIST in October 2021, he learned he had this once-drug-resistant mutation. His doctor at Loyola Medicine in Maywood, Illinois, told him he wouldn’t respond to first-line Gleevec and that he would be taking Ayvakit instead.

But Gilhooly didn’t like the sound of this new drug.

“They say it can affect your brain — your memory and cognition,” Gilhooly says. 

Gilhooly traveled to Portland to get a second opinion from Heinrich, who agreed that Ayvakit was the best option.

More than 18 months later, Brian Gilhooly’s first two post-surgery scans have shown no evidence of GIST.

“The key to managing these neurocognitive side effects is early recognition of them, modifying the dose, and doing dose interruptions,” Heinrich says.

It was decided. Gilhooly would take the drug until it shrank his tumor enough for surgery. In the end, he never had to worry about cognitive problems. After eight months on the drug, he was ready for surgery.

But Gilhooly did still get his fair share of side effects. The whites of his eyes turned yellow because of elevated bilirubin, a yellow substance the body produces during the breakdown of old red blood cells. His red blood cell count plummeted, too.

“The drug was harsh, but it killed off the tumor,” he said. “When they removed it, they said it was 90% necrotic, only 10% viable.” 

The surgeon managed to remove the entire tumor and Gilhooly was up and walking the same day. Now, more than 18 months later, his first two post-surgery scans showed no evidence of disease. He’ll continue to get scans every four months. His next one is scheduled for July.

As the treatment arsenal for GIST expands, researchers are learning the nuances of each. Not only do the current drugs target specific gene mutations, but each seems to be more effective against mutations at different locations in the tumor’s DNA.

Sutent, for example, works especially well in patients whose tumors develop resistance mutations in KIT on exons 13 and 14. Qinlock, on the other hand, does its best work in people who have primary mutations at exon 11 and secondary ones at 17 and 18.

This knowledge may drive changes in how doctors make treatment recommendations.

“We are moving toward being able to choose which option we use for a patient based on the genetics of their tumor as some drugs are more or less effective depending on the genetic characteristics of the tumor,” Brohl says.

The deeper understanding of these molecular differences is driving further research, too.

Deciphera, the maker of Qinlock, is planning a trial for patients who have developed resistance to Gleevec. They will be treated with Qinlock or Sutent based on their tumor’s DNA.

“This is the first biomarker-driven study we’ve ever done in GIST,” Heinrich says. “I expect patients would be very interested in this.” At the same time, he adds, “Another approach is to try to be more holistic by inhibiting mutations in either 13/14 or 17/18. Currently our drugs can inhibit one class but not the other – for example, 13/14 but not 17/18 or the other way around.”

Cogent Biosciences is sponsoring the phase 3 PEAK trial for patients who are resistant to Gleevec. It will compare second-line Sutent, which blocks mutations on exons 13 and 14, with and without a new drug called bezuclastinib, which is expected to inhibit mutations at 17

and 18. The trial’s crossover design will eventually allow all patients access to the combination therapy if it gets positive results.

As most patients with GIST eventually become resistant to their treatment, the newest drugs available and in the pipeline will have a significant impact. They offer patients yet another option after resistance develops. But the persistent problem of resistance shines a light on the need for additional treatment approaches.

“There’s still resistance to these drugs because they are all tyrosine kinase inhibitors that partially overlap in their mechanism of action and primarily affect the same pathways within the cell,” Brohl says. “Alternate ways to enhance treatments or avoid those shared resistance pathways are still very much needed.”

Patients with GIST have more treatment options than ever, with others currently under development.


Lining Up New Options for GIST

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.”

VHL survivor, Sean Korbitz, says that reducing the number of surgeries he has to undergo with Welireg has been “completely life-changing.”

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.

Chris de Sa has been treated for clear-cell renal cell carcinoma — with his wife, Debora, by his side — since 2015.

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

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

After being diagnosed with von Hippel-Lindau (VHL) disease, a rare tumor disorder, Sean Korbitz spent most of his 20s and 30s hoping to make it to his 60. However, after starting a new medication, he is feeling more optimistic about having a “normal life span.”

For six months in 2007, Korbitz threw up every morning and his doctors had no idea why. Suspecting a pinched nerve in his neck, Korbitz’s doctors ordered the Colorado native MRIs for his head and neck.

Sean Korbitz, a person with von Hippel-Lindau (VHL) disease, says being on Welireg (belzutifan) makes him feel like a “medical miracle”. 

Within a couple of hours, he was undergoing emergency surgery. The MRI revealed that Korbitz had a brain tumor that had been growing for six months.

In today’s episode of the “Cancer Horizons” podcast, Korbitz explains what it was like to receive a diagnosis of a rare genetic disease     

as a young adult, how his life has changed since going on Welireg, his work with the VHL Alliance, his advice for patients with VHL disease and more.

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

Podcasts

When Sean Korbitz was a 20-year-old college student, his life trajectory changed with a rare cancer diagnosis, resulting in the removal of 40 tumors; fifteen years later, a new drug made him feel like a “medical miracle.”  

Sonya Collins

Organ-Sparing Treatments Bring New Life After Cancer

Lining Up New Options for GIST

A Sea Change in Treatment for von Hippel-Lindau Disease

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

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