It is fortunate that, in a majority of cases, kidney cancer is caught before spreading to other parts of the body. For these patients, treatment usually involves a nephrectomy, which is the surgical removal of one or both of the kidneys. The goal of the surgery is to prevent the cancer from metastasizing. Unfortunately, many people who undergo a nephrectomy for high-risk disease—between 20% to 50%, according to recent estimates—will eventually go on to develop metastatic cancer.
Until recently, there wasn’t much a person’s care team could do in this situation to stop the cancer from coming back. Reliably effective “adjuvant” immune therapies—something added to surgery to prevent the cancer’s return—had not yet been identified. But in 2021, the New England Journal of Medicine published the results of a groundbreaking clinical trial. The trial involved roughly 1,000 people undergoing nephrectomy who were at high risk for cancer recurrence. About half of the people took a placebo pill, while the other half took a kidney cancer drug called pembrolizumab. Pembrolizumab is an immune checkpoint inhibitor—a type of immunotherapy drug that stimulates the immune system to fight cancer cells. After two years of follow-up, the people in the trial who took the immunotherapy drug were significantly less likely to have had a cancer recurrence than those taking the placebo. A few months later, the U.S. Food and Drug Administration (FDA) approved pembrolizumab as a form of adjuvant therapy.
“This was a win-win situation,” says Dr. Toni Choueiri, one of the leaders of that trial and director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston. Not only did the people involved in the trial benefit from the drug, but the experiment’s findings also helped expand the medical community’s knowledge of the disease and its arsenal of weapons.
Clinical trials like the one Choueiri led are happening all the time across the country. They are a necessary step—and usually the final step—in the development of new medicines for the treatment of kidney cancer. But they don’t always involve drugs. Clinical trials are also used to vet the effectiveness of new surgical techniques, new diagnostic procedures, and anything else that could improve the lives of people with kidney cancer. While some trials break new ground, others examine small changes to the existing standards of care—such as adjusting the dose of a drug up or down, or changing the way treatment side-effects are managed. In all cases, a trial’s results help shape the way every person who develops kidney cancer is treated, and so their importance cannot be overstated.
Here, Choueiri and other kidney cancer specialists detail the latest developments in the trial landscape. They also explain who is eligible to participate in clinical trials, how enrollment in a trial works, and how trials have helped revolutionize the field of kidney cancer medicine.
Mapping the current trial landscape
Kidney cancer doesn’t respond well to conventional cancer treatments, such as standard radiation or chemotherapy. As recently as 2005, there was only one type of medication—an immunotherapy medicine called interleukin-2—that had FDA approval for the curative treatment of kidney cancer.
Thankfully, the situation today is much different. “We now have more than a dozen FDA-approved drugs, and every single one of them has been approved and is available because of randomized clinical trials,” says Dr. James Brugarolas, director of the Kidney Cancer Program at the University of Texas Southwestern Medical Center in Dallas.
Brugarolas is involved in translational research, which aims to bring scientific discoveries made in the lab or in animal models into the realm of human medicine. Some of his recent work has involved a transcription factor called HIF-2. A transcription factor is basically a protein molecule that controls the activity of a gene, and HIF-2 regulates a gene that affects the growth of kidney cancer tumors. For years, there was speculation that blocking the activity of HIF-2 could stop or slow the growth of kidney cancer. However, because of HIF-2’s unusual structure, typical drugs could not bind to it. HIF-2 was basically “undruggable,” Brugarolas says. But several years ago, researchers at UT Southwestern identified a cavity in an HIF-2 protein that could be exploited with specially designed drugs. Brugarolas has helped develop those drugs, which are called HIF-2 inhibitors, and a series of clinical trials has demonstrated that they are effective for several types of kidney cancer. “Very few cancer drugs target transcription factors, so this is a new paradigm,” he says.
Brugarolas notes that clinical trials on HIF-2 inhibitors are ongoing, and similar trials are looking at many other novel drug treatments. Like other forms of cancer, kidney cancer isn’t really one disease, he says. It’s more accurate to call it a family of related cancers that have diverse characteristics. Some of his other work, including clinical trials he’s led, has examined these characteristics to determine how certain patient groups will respond to certain therapies.
While some clinical trials examine groundbreaking new treatments, others involve new cocktails of existing drugs. This sort of “combination therapy” is an especially active area of kidney cancer research, says Dr. Eric Jonasch, a kidney cancer specialist and professor of genitourinary medical oncology at MD Anderson Cancer Center in Houston. A handful of combinations have already received FDA approval. “More combinations are coming down the pipeline, and not just doublets, but triplets.”
Not all the trial work is concerned with drug treatments. “There have been advancements in surgical techniques, such as robotic surgery,” Jonasch says. A specialized type of radiation therapy is another promising area of research. “The ability to focus radiation while minimizing collateral damage has significantly improved,” he says. Radiation could offer improvements over broader “systemic” treatments for people with kidney cancers that have metastasized. “It could even treat kidney tumors themselves without surgery,” he adds.
The benefits of all this trial work are significant—and quantifiable. “Kidney cancer is a disease where, maybe 15 years ago, someone diagnosed with stage 4 disease had just one year to live, and now the average is closer to five years,” Choueiri says. The next decade is sure to bring more substantial improvements in the lives and longevity of people with kidney cancer. But to get there, clinical trials need participants.
The benefits of participating in a clinical trial
The precise risks and rewards of clinical trial participation will vary from one patient—and trial—to the next. But broadly speaking, experts say there are two compelling reasons for people with kidney cancer to take part in this type of medical research.
“Number one, trial participation may give patients the opportunity to access therapies that might not otherwise be accessible to them,” Jonasch says. In nearly all cases, the cost of these therapies—which can be considerable—will be picked up by the companies or institutions running the trial.
For those who may be concerned about trying an experimental treatment, Jonasch says that every clinical trial must be approved by a review board—an unaffiliated group of experts who scrutinize the proposed trial to ensure that participants are not exposed to undue risks. “Because of how ethical boards function today, you’re very likely going to get something that is either equivalent or superior to standard care,” he says. Research in the Journal of the National Cancer Institute has found that people with cancer who participate in clinical trials tend to fare slightly better than those who don’t. Especially for those with advanced cancers with a poor prognosis, trial participation can be beneficial, that study found.
It’s not an exaggeration to say that taking part in a clinical trial has meant the difference between life and death for some participants. “I have a lot of patients who were involved in clinical trials of small-molecule [drugs] or immunotherapies who, if they had gotten the standard of care back then, would not be alive right now,” Choueiri says.
Another benefit to trial participation is the impact its findings have on the cancer community. “You’re contributing to the expansion of our knowledge of the disease, and you’re helping in the development of therapies that will benefit other patients,” Jonasch says.
One of the tragedies of cancer is that, in many cases, it robs the world of all the good someone may have done had their life not been disrupted or cut short by the disease. “For many patients, life has been significantly undermined by cancer, and they may appreciate the opportunity to help other people who have the same disease,” Brugarolas says.
How to take part in a clinical trial
The first step is to ask your care team if you may be a good candidate for a clinical trial, Choueiri says. Referral from a cancer specialist or physician is the most common route to trial enrollment.
However, you may also have to do a little research on your own. “The entire field of oncology, not just kidney cancer, is expanding at a rate where it’s very hard to know everything that’s going on,” Choueiri says. If you’re not being treated at a major research hospital or health system, your care team may not be aware of trials that could benefit you.
There are a variety of ways to find trials on your own. “Visit ClinicalTrials.gov,” Jonasch suggests. This is a comprehensive database of clinical trials taking place in the U.S. and in other parts of the world. You can search it based on your type of cancer and your location, and it could help you find trials that are worth flagging to your doctors.
Jonasch also recommends connecting with kidney cancer patient advocacy organizations, such as the Kidney Cancer Association and the International Kidney Cancer Coalition, to ask about clinical trials. “These groups can be a tremendous resource for navigating these waters,” he says.
Finally, he says there is an especially great need for more trial participation among people of color, who are not always appropriately represented in this work. He blames problems of access and recruitment for these shortfalls. “We’re not getting it right yet, but there are efforts underway to ensure we’re reaching out to communities that may not have access to clinical trials,” he says. “It’s extremely important that we have representative diversity to ensure we understand the effects in all patient groups.”
Clearly, there’s a lot going on in the trial space for kidney cancer. It’s a safe bet that more breakthroughs may soon follow.