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Kidney Cancer

What Is Kidney Cancer?
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What’s New in Kidney Cancer Research?

Research into the causes, detection, diagnosis, and treatment of kidney cancer (renal cell carcinoma, or RCC) is being done at many medical centers, university hospitals, and other institutions around the world. A few examples of these are discussed here.

Genetics of kidney cancer

Local forms of treatment, treatment options for advanced non-clear cell renal cell carcinoma, targeted therapy and immunotherapy, tests and other factors to help determine treatment options.

Researchers are learning more about the gene changes inside kidney cells that cause them to become cancer cells. Knowing about these changes has helped doctors better classify kidney cancers into different types, which can sometimes affect treatment choices. This information has also helped researchers develop newer drugs that specifically target some of these changes inside the cancer cells (see below).

Many kidney cancers can be treated by removing or destroying the tumor(s). Treatments such as surgery, ablative treatments, and radiation therapy can be helpful in different situations. Doctors are developing newer approaches to these treatments. For example:

Surgery to remove kidney cancer can now often be done using robotic-assisted laparoscopic surgery, in which the surgeon sits at a panel in the operating room and controls very precise robotic arms to do the surgery.

Newer types of ablative treatments , such as microwave ablation and irreversible electroporation, are now being studied for use in destroying tumors in the kidneys or other parts of the body.

Newer forms of radiation therapy , such as stereotactic body radiation therapy (SBRT), are now an option to treat some tumors.

The most common type of kidney cancer is clear cell RCC . A small portion of kidney cancers, called non-clear cell RCCs , are different subtypes, which might respond better to different types of treatment than those used for clear cell RCC. Doctors are now studying which treatments might be most helpful for these cancers.

In the last couple of decades, newer types of drug treatments have emerged as the most effective treatment options for most advanced kidney cancers.

Targeted drugs attack specific parts of cancer cells (or nearby cells that help them grow, such as the cells that make new tumor blood vessels).

Immunotherapy drugs help the body’s own immune system find and attack the cancer cells.

These types of drugs, alone or combined, are now usually the main treatment options for kidney cancers that can’t be removed completely with surgery. Doctors are now studying which combinations of drugs might work best.

Newer types of targeted and immunotherapy drugs are being developed. For example, CAR T-cells are a person’s own immune cells that have been altered in a lab to attack a target on cancer cells. Researchers are now looking to see if CAR T-cells designed to attach to the CD70 protein on cancer cells can be helpful in treating advanced RCC.

Adjuvant therapy

Doctors are studying if giving additional (adjuvant) treatment after surgery can help lower the risk of kidney cancer coming back, especially when there’s a higher risk this might happen. For example, getting the immunotherapy drug pembrolizumab (Keytruda) for about a year has been shown to help lower this risk in some people, especially those with clear cell RCC. Other medicines are being studied as well to see if they can lower this risk.

Neoadjuvant therapy

Doctors are also studying giving drug treatments such as immunotherapy or targeted therapy before surgery (called neoadjuvant therapy ).

For some people whose cancer can be removed, it might shrink the tumor(s). This might let the doctor do a less extensive surgery, and it might help lower the risk that the cancer will come back.
For some people whose tumors can’t be removed completely with surgery, it might shrink the tumor enough that surgery can be done.

Studies are being done to see which people might benefit the most from neoadjuvant therapy (as well as which drugs might be most effective in this setting).

Along with looking for new medicines and the best ways to combine and use existing ones, a major area of research is finding better ways to choose the best treatment for each person.

Researchers are looking at whether certain lab test results or other factors might make a person's cancer more (or less) likely to respond to certain medicines. Knowing this can help doctors give treatments that are more likely to be helpful, while avoiding giving those that aren’t (but that could still have side effects).

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Atkins MB. Overview of the treatment of renal cell carcinoma. UpToDate. 2023. Accessed at https://www.uptodate.com/contents/overview-of-the-treatment-of-renal-cell-carcinoma on December 13, 2023.

Choueiri TK, Pal SK. The treatment of advanced non-clear cell renal carcinoma. UpToDate. 2023. Accessed at https://www.uptodate.com/contents/the-treatment-of-advanced-non-clear-cell-renal-carcinoma on December 15, 2023.

Graham J, Heng DC, Brugarolas J, Vaishampayan U. Personalized management of advanced kidney Cancer. Am Soc Clin Oncol Educ Book. 2018; 38: 330-341 .

McNamara MA, Zhang T, Harrison MR, George DJ. Ch 79 - Cancer of the kidney. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology . 6th ed. Philadelphia, Pa: Elsevier: 2020.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. V1.2024. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf on December 15, 2023.

Last Revised: May 1, 2024

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FDA Approves New Treatment for Advanced Kidney Cancer

Welireg improved progression-free survival for previously treated people with inoperable renal cell carcinoma.

December 18, 2023 • By Liz Highleyman

The Food and Drug Administration last week approved Welireg (belzutifan) for patients with advanced kidney cancer who previously used other types of treatment. The December 14 decision marks the first approval of a new class of therapy for advanced renal cell carcinoma (RCC), the most common type of kidney cancer, in nearly a decade.

Welirig is a hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor, a type of targeted therapy. It interferes with a transcription factor that regulates genes that promote adaptation to hypoxia, or low oxygen. Overproduction of HIF-2α can promote tumor growth. Welireg was initially approved in August 2021 for adults with von Hippel-Lindau disease who require treatment for RCC, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors.

Approval for the new indication was based on results from the LITESPARK-005 trial ( NCT04195750 ), which enrolled 746 patients with inoperable locally advanced or metastatic clear cell RCC that had progressed after trying both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF tyrosine kinase inhibitor. The participants were randomly assigned to receive Welireg or Afinitor (everolimus), both administered as once-daily pills.

People who received Welireg saw a statistically significant improvement in progression-free survival (PFS)—reflecting a 25% lower risk of disease progression or death—though the median PFS time was the same in both groups (5.6 months). The overall response rate was 22% in the Welireg group versus 4% in the Afinitor group. Among those with a confirmed response, the median duration of response exceeded one year. Overall survival results are not yet mature.

Patient-reported outcomes suggested that Welireg may be better tolerated than Afinitor, but side effects were common in both groups. The most frequently reported adverse reactions among people taking Welireg are anemia, fatigue, musculoskeletal pain, low white blood cell counts and various laboratory abnormalities. About 6% stopped treatment due to adverse effects. Welireg can cause severe hypoxia, so oxygen saturation levels should be monitored.

“Despite recent progress in the treatment of advanced RCC, there is yet to be an option specifically approved for patients whose disease progresses following a PD-1 or PD-L1 inhibitor and a TKI therapy,” trial investigator Toni Choueiri, MD, of Dana-Farber Cancer Institute, said in a Merck news release . “This approval of belzutifan introduces a meaningful new treatment option for certain patients, as belzutifan reduced the risk of disease progression or death compared to everolimus.”

Click here for full prescribing information for Welireg .

Click here for more news about kidney cancer .

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FDA approves kidney cancer therapy after Dana-Farber-led research shows improved outcomes for patients with advanced disease

Belzutifan, a HIF-2α inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced kidney cancer previously treated with immune checkpoint inhibitors and anti-angiogenic therapies.

The FDA approval was based on results of the phase 3 LITESPARK-005 trial , a study led by Toni K. Choueiri, MD , director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute.

Findings from LITESPARK-005 were presented at the European Society of Medical Oncology annual meeting in October 2023. Researchers reported belzutifan significantly reduced the risk of progression of clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, in this patient population. The trial compared belzutifan to everolimus and the data showed the risk of progression was reduced by 26%. Responses were 6 times higher with belzutifan compared to everolimus.

"This approval is exciting news for our patients as it gives us a new option for refractory patients with kidney cancer," said Choueiri. "Belzutifan is an oral drug with a novel mechanism of action that reduced risk of disease progression or death and had favorable quality of life in this patient population, when compared to everolimus."

Previously, the FDA approved belzutifan for patients with Von Hippel-Landau (VHL) disease-associated renal cell carcinoma, a rare form of kidney cancer. The drug was originally investigated and approved for kidney cancer patients with VHL disease because they have inherited a mutation that inactivates the VHL gene, which results in an overabundance of HIF-2α in cells.

When overabundant in cells, HIF-2α is associated with increased cancer-driving activity, such as cell proliferation, immune evasion, low oxygen levels (called hypoxia), and blood vessel formation (called angiogenesis). Dana-Farber’s William G. Kaelin, Jr., MD, was awarded a Nobel Prize in Physiology or Medicine in 2019 for the discovery of the role HIF-2α in cancer and other diseases.

LITESPARK-005, enrolled 746 patients with metastatic ccRCC who had progressed after treatment with both an immune checkpoint inhibitor (ICI), such as a PD-1 or PD-L1 inhibitor, and an anti-angiogenic therapy. ICIs and anti-angiogenic medicines have become a standard part of first- and second-line therapies for metastatic ccRCC, though most patients eventually experience disease progression and need additional treatment options.

Patients were randomized to receive treatment with either belzutifan or everolimus. At the second interim analysis, after a median of 25.7 months, patients taking belzutifan were 26% less likely to have progressed compared with those taking everolimus.

The overall response rate was also higher with belzutifan, at 22% versus 3.5%, and 13 patients experienced a complete response with belzutifan compared to none with everolimus.

Regarding safety, findings for belzutifan were consistent with data from previously reported studies and patients taking belzutifan were less likely to discontinue therapy due to side effects.

The trial is sponsored by Merck Sharp & Dohme LLC.

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A CT scan of a healthy kidney. Kidneys filter waste from the bloodstream and control the level of certain helpful chemical substances.

Major developments in kidney cancer in 2021

2021 was a bumper year for kidney cancer developments, including several new treatment approvals by the FDA and a much better understanding of how kidney cancer is impacted by COVID-19 infections and vaccines.

“All are very important topics that are affecting patients as we speak,” said Nancy Moldawer, RN, of Cedars-Sinai Medical Center in Los Angeles, Ca, and a member of the KCA’s Clinical Advisory Board. “Between deciding what first line therapy to chose from to the concern of the genetic risk of renal cell carcinoma, are all very real concerns to patients.”

We rounded up the major developments in kidney cancer this year, focusing on those with the greatest impact or potential impact for people facing kidney cancer.

Drug Information

New drug approvals or new regimen approvals

Pembrolizumab (Keytruda) was approved for treating renal cell carcinoma (RCC) patients who are at risk of disease recurrence after a nephrectomy or after a nephrectomy and removal of other metastatic lesions). Read more.
Belzutifan (Welireg) was approved as the first-ever treatment for people with RCC (and other tumor types) associated with Von Hippel-Lindau (VHL) disease. Read more.
Lenvatinib (Lenvima) plus pembrolizumab was approved for first-line treatment in advanced RCC. Read more.
Tivozanib (Fotivda) was approved for adults with relapsed or refractory advanced RCC after they’ve received two or more prior systemic therapies. Read more.
Nivolumab (Opdivo) plus cabozantanib (Cabometyx) was approved as first-line treatment in advanced RCC. Read more.

“Scientifically, I think the belzutifan [approval] is most important. It’s the only agent for which there’s truly a new target,” said Dr. Walter Stadler, a medical oncologist at the University of Chicago Medical Center, though he noted researchers don’t know how useful it will be for people with non-VHL-related tumors. Belzutifan targets and inhibits the hypoxia-inducible factor-2 alpha (HIF-2α) protein, which is involved in regulating cellular oxygen levels, a pathway that VHL disease and related cancers can be sensitive to.

“We should be closely watching how the belzutifan story develops as it is tested as monotherapy and in other clinical combinations,” said Dr. Chung-Han Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York.

Both Lee and Stadler noted adjuvant pembrolizumab was an important development and one to monitor. When data from the phase III KEYNOTE-564 trial, on which the FDA approval was based, was presented at ASCO 2021 , lead researcher Dr. Toni Choueiri of the Dana-Farber Cancer Center in Boston said the results could make pembrolizumab a potential new standard of care after nephrectomy. However, Stadler said the current evidence showing improved disease-free survival in some patients but not improved overall survival still makes adjuvant treatment a controversial choice.

“It will benefit a few people to delay recurrence,” Stadler said. “The real question is, does it matter if I treat in an adjuvant, or preventive, manner versus treating only those patients who recur? If the ultimate survival for the cancer is the same, why expose people to toxic therapy now?”

Lee flagged the CANTATA and PAPMET trials, both with results presented in the past year, as deserving mention. CANTATA was a disappointment in that the glutaminase inhibitor telaglenastat did not improve patient outcomes. Telaglenastat may have represented a new approach to kidney cancer treatment but Lee said the compound and glutaminase inhibition are still paths to explore for kidney cancer. Thephase II PAPMET trial showed benefits with cabozantinib for metastatic papillary RCC, a rare subtype that didn’t have effective treatment options. This regimen is now part of the National Comprehensive Cancer Network’s guidelines for treating papillary RCC.

“The rate of improvement [in patient care] is rapidly accelerating, not only with novel combinations and new drug classes, but also new disease states in which treatment is helpful,” said Dr. Chung-Han Lee.

According to Dr. Tian Zhang, a medical oncologist at UT Southwestern Medical Center, both the adjuvant pembrolizumab and belzutifan approvals “represents a direct result from National Cancer Institute and pharmaceutical resources, scientific advances, cancer researchers, and patients who have generously participated in clinical trials. Scientific discoveries in understanding the biology of kidney cancer are directly translating into new treatment options for our patients.”

When looking to the future, Zhang said ongoing trials in first-line kidney cancer that address treatment sequencing approaches and combination trials in the perioperative or adjuvant setting will be areas to watch.

Stadler included belzutifan in non-VHL clear cell RCC settings, survival outcomes over several years with adjuvant pembrolizumab, triplet therapy and whether it is worth the increased toxicity, and long-term survival with immunotherapy as well as discontinuing immunotherapy (especially the ipilimumab/nivolumab combination) in that list. The latter in particular, he said, would help answer the question of whether researchers are getting closer to a cure for some patients.

Covid-19 vaccines are safe and effective for people with cancer

A number of studies, many of which were presented during the 2021 Congress of the European Society for Medical Oncology (ESMO) , showed people with cancer – including kidney cancer – have appropriate immune response to COVID-19 vaccination and that vaccination is safe in these patients, even those who are undergoing treatment with chemotherapy and/or immunotherapy. Read more.

Consensus statement on genetic risk assessment for inherited RCC answers who should get genetic risk assessment and what types of tests they should get

In late 2019, a group of 33 researchers, healthcare providers, and advocates with expertise in hereditary RCC came together to determine how to care for patients with suspicion of an inherited form of kidney cancer. Though the resulting guidelines, published in the August 2021 edition of the journal Cancer , may not account for all the scenarios where a genetic risk assessment would be useful, the group attempted to clarify for whom, when, and how genetic risk assessment should be performed. Read the guidelines.

There was strong agreement for the following issues:

People with certain kidney tumors (papillary type 1, chromophobe, renal angiomyolipomas and clear cell RCC) in both kidneys or multiple tumors in one kidney
People with hybrid renal tumors (oncocytomas/chromophobe), SDH-tumors, or FH-deficient tumors
People with more than 1 of the following tumors outside the kidney: pheochromocytoma or paraganglioma, endolymphatic sac tumor, uveal melanoma, and FH-deficient uterine fibroid
Certain people with 1 st and/or 2 nd degree relatives with RCC or features suggestive of an inherited cancer syndrome.
Anyone undergoing testing should have pre-test counseling by someone with expertise in inherited cancer syndromes either in-person or by telemedicine.
If there are signs of a specific condition, only that gene should be tested, otherwise a test of multiple genes should be done in those with more general risk factors.
Single gene testing by blood is also preferred following the finding of a mutation in the tumor itself in order to check for it being an inherited form or when pretest counseling cannot be done.

Dr. Christopher G. Wood, chair of the KCA’s Board of Directors, dies

Dr. Christopher G. Wood, a urologic surgeon at MD Anderson Cancer Center in Houston, Texas and Chair of the KCA’s Board of Directors, died on November 3, 2021 after an unexplained neurologic condition. The outpouring of grief, support, memories, and gratitude for his gifts as a surgeon and mentor showed how pivotal Dr. Wood was to the kidney cancer community. During a memorial at the 2021 IKCS: North America in Austin, Texas immediately after Dr. Wood died, his friend and fellow KCA board member Dr. Bradley Leibovich said: “Chris was an unbelievably dedicated, superb surgeon who was always striving for excellence in the operating room… because Chris cared about his patients deeply. His compassion for people was truly remarkable. He was absolutely dedicated to being the best he could possibly be at all points in time in service of his patients.”

Within the KCA, Dr. Wood was a force nearly since its inception in the early 1990s, helping to shape it into the international awareness, advocacy, and support organization it is today. The KCA’s Dr. Christopher G. Wood Endowment will help continue his life’s work in kidney cancer as a clinician, researcher, educator, and mentor. Learn more and contribute.

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4 thoughts on “Major developments in kidney cancer in 2021”

Hi. My dad only had a bit of back pain. He finally went in to get it looked at and he has been diagnosed with stage 4 renal cell carcinoma that has metastasized to his spine. We are still partially in shock and also desperate to get him started with a promising treatment. If anyone has any information that might help us it would be greatly appreciated. We sent all his scans and imaging and have an appointment for the mayo clinic but they can’t get us in any earlier then Aug.8. Given the dire circumstances I don’t think that will work as we would be looking at over a month before he even gets an appointment with them. We are from Canada and the waiting here over the last 2 weeks just to get biopsy and ct scans are awful. My dad is only 66 and has always been healthy. This is such a shock how it can be this bad with no symptom other than sore back. I appreciate any help or slight bit of hope. My family and I appreciate it.

Dear Melissa, I’m your fathers age, perfectly healthy,sore back flank ache, RCC 18 months ago. May I recommend UPMC in Pittsburgh . They have a RCC expert,Dr Leonard Appleman. He’s aDana Farber fellow and has me and several others I’ve met with RCC on an Immunotherapy combination post surgery( left kidney removed, metastasis to one lung and nodes.) We are all doing fine and we’re stage 3-4. You may like his team.Feel free to contact me. Happy to help.

Jack, I find myself in a similar situation as yours. My left kidney, metastasis to my lung, or lungs. I just found out in an emergency room CT scan last week. Thank you for sharing you are doing well. Scott

Hello, I am from another part of the globe but my dad just got diagnosed with an 8cm tumor, suffered a complete nephrectomy (he is 61) Can you tell me the name of the drugs and how are you feeling now? Thank you!

The Latest Breakthroughs That Could Improve Kidney Cancer Treatment

human kidneys disease anatomy outside 3d rendering image Concept of urinary system image

D r. David McDermott started treating people with kidney cancer in the 1990s. Back then, he says the prognosis for most of his patients with advanced disease was dispiritingly grim. “We had very few treatment options, and the survival for patients was a year or less,” he recalls. “Radiation and chemotherapy were tried, but they didn’t work.”

Things began to change when researchers discovered that kidney cancers were highly “angiogenic” compared to most other forms of cancer, meaning that kidney tumors are rich in blood vessels. This insight supported the development of angiogenesis inhibitors, a type of drug that cuts off the blood supply to these tumors. “These drugs were very effective because of the biology that drives most kidney cancers,” says McDermott, a professor of medicine at Harvard Medical School and a cancer specialist at Beth Israel Deaconess Medical Center in Boston. Life expectancies doubled—a great leap forward, but one that still left plenty of room for additional improvement.

A more significant breakthrough—one that some cancer researchers say has revolutionized the treatment of kidney cancer—arrived just a decade ago. “The big innovation that changed things was immune checkpoint inhibitors,” McDermott says. Many cancers, including kidney cancers, have built-in defenses that allow them to repel the human immune system’s attacks. Immune checkpoint inhibitors help thwart these defenses. “If you think of a tumor’s defense against an immune attack as barbed wire, this class of immunotherapy drugs aims to cover the barbed wire and allow the immune system to do its job,” he explains.

Kidney cancers are among the top 10 most common cancers in both men and women: about 79,000 new cases will be diagnosed in 2022, according to the American Cancer Society. When the cancer is first diagnosed, more than 20% of patients already have advanced disease, meaning the cancer has spread beyond the kidneys. Even among those whose cancer is confined to the kidney and who undergo surgery, 30% will eventually develop metastatic disease.

Immune checkpoint inhibitors remain one of the primary treatments for kidney cancers , and recent developments in the science of these drugs remain a big story in treatment advancements. But it’s not the whole story. Here, McDermott and other experts described the current care landscape, including the latest innovations.

Unshackling the immune system

Thirty years ago, the American immunologist Jim Allison led research efforts that revealed the existence of immune checkpoints. Specifically, he and colleagues found that a protein on the surface of immune system T cells acts as a checkpoint, or brake, to prevent an overzealous immune system response.

Allison’s work led to the discovery that cancer cells take advantage of these checkpoints in ways that allow them to limit or evade the human body’s built-in protections. These insights have led to the creation of medicines that have changed the face of cancer care, including for kidney cancers. “The work of professor Jim Allison opened the field for immune checkpoint inhibitors and other immune therapies, which has led to the golden era of immunotherapy that we’re now seeing,” says Dr. Nizar Tannir, an oncologist and cancer researcher at the University of Texas MD Anderson Cancer Center in Houston. The U.S. Food and Drug Administration (FDA) approved the first immune checkpoint inhibitor for the treatment of kidney cancer in 2015. Since then, more of these drugs have received FDA approval. They target CTLA-4, PD-1, and PD-L1—proteins on immune cells that can limit the immune system’s attacks against cancer cells.

Even among people who don’t have metastatic kidney cancer, immune checkpoint inhibitors are now being tested as a therapy after kidney surgery. “Patients with kidney cancer that is confined to the organ usually undergo nephrectomy,” Tannir says, referring to a surgery that involves the removal of the kidney. “Just last November, the FDA approved pembrolizumab in patients who have a high risk of relapse after nephrectomy.” That approval came after a clinical trial showed that patients who got pembrolizumab were significantly more likely to be alive and disease-free two years after surgery compared to those who got a placebo.

While immune checkpoint inhibitors began as “second-line” therapies, to be used only after other treatments have failed, they’re increasingly being used as first-line therapies. “This is probably the biggest innovation of the last five years,” McDermott says. One of the interesting things about immune checkpoint therapy, he explains, is that some of the best-responding patients are the ones with the most aggressive tumors. “This is the opposite of what you would see with chemotherapy, where patients with more indolent tumors often benefit more,” he says. Why does this happen? One of the theories is that aggressive cancers may look very different than normal tissues, and so the immune system, once its brakes are released, is better able to locate and attack these tumors. Because some kidney cancers are fast-developing, starting immune checkpoint therapy as soon as possible can be preferable. “By giving immunotherapy early, as first-line treatment, more patients are not dying early,” he says.

Another advancement in immunotherapy involves using combinations of these drugs—either with one another or with other kidney cancer medications—instead of deploying them alone. Right now, McDermott says it’s more common to combine a single immune checkpoint inhibitor with the older class of kidney cancer drugs (the angiogenesis inhibitors). “This is a fusion of the old first-line therapy—the blood vessel-targeting drugs—with the new first-line therapy,” he says. “When you put them together, most of the benefit is additive, but in some patients it can also be synergistic.” In other words, the drugs may work better together than either would be when used independently.

While using two or more immune checkpoint inhibitors in combination is less common, some combinations are approved for use in both the U.S. and Europe. McDermott says he’s a proponent of this approach despite the greater potential for adverse reactions. “Blocking two of these immune checkpoints instead of one can dramatically increase the immune response to both the tumor and to normal tissues,” he says. “So it appears to increase the chances of disease remission, but it also increases the chances of toxicities.”

How much does that risk of toxicity increase? When taking one immune checkpoint inhibitor, he estimates that roughly 1 in 10 patients is forced to stop the treatment due to side effects, which can include joint pain, gut dysfunction, and other debilitating symptoms. This rate doubles to 2 in 10 when a second immunotherapy is added. Even short of having to stop treatment, the side effects tend to be more severe when someone is taking multiple immunotherapies. “It really comes down to philosophy of the appropriate goals of therapy,” he says. “Most oncologists don’t think kidney cancer is a curable disease.” As a result, he says they tend to opt for drug combinations with a milder side-effect profile and good near-term results. “I would argue that the longer-term outcomes are better with a combination of immune checkpoint inhibitors, but comparative trials are warranted to formally resolve this important debate,” he says.

Other experts share his view that combinations of immune therapies may provide the best chance for long-term survival. “If you look at median survival 10 years before the first immune checkpoint inhibitor was approved, clinical trials reported median overall survival of 20 to 30 months for patients with newly diagnosed metastatic cancer,” says Dr. Martin Voss, a clinical director and kidney cancer specialist at Memorial Sloan Kettering Cancer Center in New York City. Citing the latest research on combination treatments using immune checkpoint inhibitors, he says median survival is estimated to be 50 months or more for most patients. “So that’s almost double what it was, and a much higher percentage of patients are able to achieve complete remission,” he says.

This last point hints at a compelling area of kidney-cancer research. Why do some patients respond so well to the current drugs—in some cases, the cancer is eradicated—while others don’t? Advancements in tumor profiling and kidney cancer biomarkers—a catchall term for the cancer’s traits or characteristics—may help solve this puzzle.

Read More: Coping With the Side Effects of Kidney-Cancer Treatment

Unmasking the enemy

A major theme in cancer research—and not just for kidney cancers—is the recognition that the disease is highly variable. Voss says that kidney cancer comes in different “flavors,” or molecular subtypes, that help experts understand how the cancer evolves and why it may respond to different types of treatment. By studying kidney cancer biomarkers, he and other experts hope they’ll be able to better predict which patients do best on specific drugs or drug combinations.

“Some tumors seem to be more dependent on metabolism being changed in certain ways, while others are greatly dependent on tumor vasculature,” he says. Understanding these sorts of variations and their treatment ramifications, and also identifying ways to assess the presence of these variations in people with kidney cancer, is critical to improving outcomes. Scientists are studying how to better address these variations “to match people with the right treatment,” he says.

Kidney biomarkers and subtyping can also help improve the science of targeted therapies (including immunotherapies ) for kidney cancer. “If you understand what’s happening on the surface of the cancer cells, you can deliver much more directed therapies and achieve a much more potent immune response,” Voss says. For example, chimeric antigen receptors, or CARs, are molecularly engineered proteins that are designed to bind to a cancer cell (but not healthy cells) and summon an immune response. While these have been used successfully for other cancers, they’ve only recently made their way into clinical kidney cancer trials. “The whole field is holding its breath for those results, which we should have in the next year or two,” he says. These could provide another big leap forward in kidney cancer treatment.

Read More: 4 Important Steps to Take After a Cancer Diagnosis

More reason for optimism

There’s a lot more going on in kidney cancer care. McDermott says another promising advancement involves a class of drug known as hypoxia inducible factor (HIF)-2α inhibitors. HIF-2α helps cancerous tumors develop new blood vessels, use nutrients more efficiently, and otherwise adjust in ways that support their spread and survival. HIF inhibitors are drugs that can block all of these adjustments. “Early results of these HIF-2α agents are encouraging,” he says. Meanwhile, he says that many novel immunotherapies and targeted therapies are also in development.

Taking a 10,000-foot view, it appears that the treatment foundations have been laid—and in some cases, impressively built upon—that will eventually lead to reliable remission for most people with advanced kidney cancers. Already, once-deadly cancers are being succesfully treated. Looking ahead, the evolution of cancer subtyping and biomarker mapping should help ensure that patients are given the most effective drugs with the lowest risk of side effects. Considering how dramatically the treatment picture has changed in just the last five or 10 years, there’s reason to expect more significant advancements in the near future.

As MD Anderson’s Tannir says, “There is more hope than ever for patients to have improved survival, and even a complete and durable remission with the potential for cure.”

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September 17, 2024

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Combination treatment doubles survival for patients with advanced kidney cancer

by Ernie Mundell

Combo treatment doubles survival for patients with advanced kidney cancer

A small clinical trial suggests that a duo of drugs can extend survival for people battling advanced kidney cancer.

Researchers at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., developed the new regimen, a combination of pazopanib ( Votrient ) and bevacizumab ( Avastin ).

Pazopanib is from a class of cancer drugs known as tyrosine kinase inhibitors (TKIs). These drugs work by blocking vascular endothelial growth factor (VEGF) signaling—a key mechanism that cancer cells need to grow.

In prior trials that led to pazopanib's approval by the U.S. Food and Drug Administration, the drug led to an average survival (without cancer progression) of just over 11 months among people diagnosed with kidney tumors.

The new trial, which involved 51 patients, found that combining pazopanib treatment with bevacizumab doubled that progression-free survival , to more than 23 months, on average.

Patients received pazopanib and bevacizumab in 10-week treatment cycles.

They first underwent treatment with pazopanib during days one to 28.

As a team led by Dr. Saby George explained, pazopanib works by shutting down VEGF, but any increase in VEGF can lead to cancer cell resistance against the drug.

So, patients got bevacizumab midway through the 10-week cycle (days 36 to 50), since that drug "neutralizes" VEGF—potentially extending pazopanib's cancer -fighting power.

The strategy appears to have worked, greatly boosting survival among those patients who received it.

Some patients with advanced kidney cancers were good candidates for powerful immunotherapy cancer medicines, but George's team noted that pazopanib/bevacizumab might be a safer option for some.

The combo drug therapy had "superior safety compared with immunotherapy combinations," the researchers noted in a Roswell news release.

"Because immunotherapy options were available to patients in other risk groups, the Phase II group included more patients in the Favorable Risk category," said George, a professor of oncology and medicine at Roswell. "The encouraging results suggest that alternating pazopanib with bevacizumab is a promising treatment regimen for renal cell [kidney] carcinoma patients in the Favorable Risk group."

The findings were presented at the European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain.

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Can Urol Assoc J
v.15(4); 2021 Apr

Management of advanced kidney cancer: Kidney Cancer Research Network of Canada (KCRNC) consensus update 2021

Christina canil.

1 Division of Medical Oncology, The Ottawa Hospital Cancer Centre and the University of Ottawa, Ottawa, ON, Canada

Anil Kapoor

2 Division of Urology, McMaster University, Hamilton, ON, Canada

Naveen S. Basappa

3 Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada

Georg Bjarnason

4 Division of Medical Oncology/Hematology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada

Dominick Bossé

Shaan dudani.

5 William Osler Health System, Brampton, ON, Canada

Jeffrey Graham

6 Cancer Care Manitoba, Winnipeg, MB, Canada

Samantha Gray

7 Department of Oncology, Dalhousie University, Saint John Regional Hospital, St. John, NB, Canada

Aaron R. Hansen

8 Department of Oncology, Princess Margaret Cancer Centre, Toronto ON, Canada

Daniel Y.C. Heng

9 Department of Medical Oncology, University of Calgary and Tom Baker Cancer Centre, Calgary AB, Canada

Pierre I. Karakiewicz

10 Department of Surgery, Le Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada

Christian Kollmannsberger

11 Division of Medical Oncology, British Columbia Cancer Agency-Vancouver Cancer Centre, and the University of British Columbia, Vancouver, BC, Canada

Aly-Khan A. Lalani

12 Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada

Scott A. North

François patenaude.

13 Department of Medicine, Hematology Service and Department of Oncology, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Montreal, QC, Canada

Denis Soulières

14 Division of Medical Oncology/Hematology, Le Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada

Myuran Thana

15 Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada

Eric Winquist

16 London Health Sciences Centre, London, ON, Canada

Lori A. Wood

M. neil reaume, ranjena maloni.

17 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada

Sebastien J. Hotte

Introduction.

For more than a decade, targeted systemic therapies have been the standard of care for metastatic renal cell carcinoma (mRCC) and their use has been refined over time as clinical experience has evolved. 1 – 6 The 2019 consensus statement by the Kidney Cancer Research Network of Canada (KCRNC) introduced the role of immunotherapy as first-line systemic therapy for mRCC, either as doublet immunotherapy or in combination with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), based on phase 3 studies that demonstrated improved survival compared to single-agent VEGFR-TKI (sunitinib). 7 – 9 Subsequently, there have been updates on two of the important previously reported phase 3 studies (CheckMate 214 and Keynote-426) that have reinforced prior results. 10 , 11 In addition, there have been two new phase 3 studies published (CLEAR and CheckMate 9ER) of immunotherapy + VEGFR-TKI also demonstrating survival benefit over VEGFR-TKI alone. 12 , 13 Furthermore, the CLEAR study showed improved progression-free survival (PFS), but not overall survival (OS) benefit, with the use of VEGFR-TKI + mammalian target of rapamycin (mTOR) inhibitor compared to VEGFR-TKI alone. These studies and updates have been included in this report. 13

The current consensus statement is based on the deliberations and conclusions of key Canadian opinion leaders in the management of advanced renal cell cancer who convened during the 11th Canadian Kidney Cancer Forum, held virtually on October 16, 2020. During that session, the authors reviewed the previous advanced disease management consensus statements, published in 2019, 7 discussed the recent relevant evidence, and reached consensus on the revised statements published below.

As noted in the discussion section of this paper, unanimous consensus was not reached for all treatment options. The published recommendations reflect the majority position for these items.

The authors recognize that the field of systemic therapy for advanced RCC is evolving quickly and remind readers that the recommendations made in this document reflect the available evidence at the time the consensus conference participants reached their conclusions (October 16, 2020). Two exceptions are the late addition of data from the CLEAR and PAPMET studies, which were presented at the ASCO Genitourinary Cancers Symposium on February 13, 2021 and concurrently published. 13 – 16 The results of these trials were reviewed by all co-authors and there was agreement to include the findings in this publication to ensure the most contemporary document and recommendations possible. As new data become available, treatment options will invariably change, and members of the KCRNC intend to update these recommendations on a regular basis moving forward.

1. Management of locally advanced kidney cancer

1.1. neoadjuvant therapy.

– There is no indication for neoadjuvant therapy prior to planned surgical resection of the primary kidney tumor outside the context of a clinical trial.

If patients are felt to have surgically resectable disease at diagnosis and are medically fit, they should proceed immediately to surgery. There is currently insufficient evidence to support a general recommendation for neoadjuvant therapy.

There have been many small studies demonstrating a potential benefit of systemic neoadjuvant approaches (mostly with VEGFR-TKIs), including modest reduction in tumor size and possible facilitation of locally advanced tumor resection and complex partial nephrectomy. 17 – 30 However, there are no randomized controlled trials to support the use of neoadjuvant therapy.

Studies investigating the utility of immune checkpoint inhibitors, VEGFR-TKIs, or their combination in the neoadjuvant setting are currently ongoing. 31 – 36 There is also a study investigating the use of a neoadjuvant vaccine in RCC. 37

In summary, there is insufficient evidence to support a specific recommendation for routine use of neoadjuvant therapy outside of clinical trials. However, some patients with advanced localized disease deemed medically or surgically inoperable at diagnosis may have a radiological and/ or clinical response to systemic therapy. A multidisciplinary team should re-evaluate these cases if there is any question that they may have converted to an operable state and are likely to benefit from nephrectomy, as discussed in section 2.4 below (“Cytoreductive nephrectomy”).

1.2. Adjuvant therapy

– The use of adjuvant therapy following nephrectomy in non-metastatic RCC patients is not currently recommended outside the context of a clinical trial.

Adjuvant therapy with cytokines (interferon-alpha) does not improve OS after nephrectomy 38 and five prospective randomized trials of VEGFR-TKIs have failed to show OS benefit for sunitinib, sorafenib, pazopanib, and axitinib. 39 – 44

The phase 3 S-TRAC two-arm, randomized, placebo-controlled trial of one year of sunitinib or placebo in patients at high risk of recurrence showed an improvement in the primary endpoint of disease-free survival (DFS) with adjuvant sunitinib comparable to the time on therapy. 40 For OS, a secondary endpoint, the most recent published update on S-TRAC reported that the median had not yet been reached for either arm, with no significant difference between sunitinib and placebo (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.66–1.28, p=0.6). 40 Quality-of-life outcomes demonstrate that on most QLQ-C30 subscales, patients in the sunitinib group had lower scores than those in the placebo group. 40 In the U.S., sunitinib was approved for use in the adjuvant setting based largely on the findings of this study. 45 Sunitinib is not approved for this indication in Canada.

As is the case in the neoadjuvant space, a number of ongoing studies in the adjuvant setting are seeking to determine the role and duration of therapy of other molecular targeted therapy (everolimus 46 ) or immune checkpoint inhibition (atezolizumab, 47 ipilimumab + nivolumab, 48 pembrolizumab, 49 durvalumab ± tremelimumab 50 ).

To summarize, to date, no clinical trial has demonstrated an OS advantage with adjuvant targeted therapy in patients with RCC after curative resection of the primary tumor. Pending additional data from ongoing adjuvant trials, patients with high-risk tumors who have undergone complete resection should not be routinely offered adjuvant systemic therapy and should be encouraged to participate in clinical trials whenever possible.

2. Advanced or metastatic kidney cancer

When recommending systemic therapy for advanced or mRCC, several key factors must be taken into account. Patients are best served if the prescribing physician is an oncology specialist knowledgeable of the disease, the drugs, acute and long-term toxicities, drug interactions, and monitoring of treatment and response. Patients should be managed in a multidisciplinary environment with adequate resources, including access to radiation oncology, surgical oncology, nursing care, dietary care, and pharmacy support.

Patients must be evaluated frequently to ensure toxicities are recognized and managed appropriately. Patients and caregivers should be provided with information concerning potential side effects, as well as their prevention and management. Participation in clinical trials is strongly encouraged.

2.1. Clear-cell carcinoma ( Table 1 )

Therapeutic options for advanced clear-cell RCC

Participation in clinical trials is strongly encouraged in all settings of treatment

Patients	Preferred	Options
Favorable-risk (IMDC)	Pembrolizumab + Axitinib Nivolumab + Cabozantinib Lenvatinib + Pembrolizumab	Sunitinib Pazopanib Axitinib + Avelumab Active surveillance
Intermediate-/poor-risk (IMDC)	Ipilimumab + Nivolumab Pembrolizumab + Axitinib Nivolumab + Cabozantinib Lenvatinib + Pembrolizumab	Sunitinib Pazopanib Cabozantinib Axitinib + Avelumab Active surveillance
Prior VEGF inhibitor	Nivolumab Cabozantinib	Lenvatinib + Everolimus Axitinib Everolimus

Prior immune checkpoint inhibitor	Axitinib Cabozantinib Lenvatinib + Everolimus Pazopanib Sunitinib
Prior VEGF and immune checkpoint inhibitor	Axitinib Cabozantinib Lenvatinib + Everolimus Pazopanib Sunitinib

“Preferred” options originated from studies that have demonstrated overall survival (OS) improvements. “Options” have usually demonstrated a progression-free survival advantage but not necessarily OS survival.

IMDC: International Metastatic RCC Database Consortium; RCC: renal cell carcinoma; VEGF: vascular endothelial growth factor.

2.1.1. Untreated patients

– Choice of initial systemic treatment is based in part on International Metastatic RCC Database Consortium (IMDC) risk status.
– For IMDC favorable-risk patients, a combination of immunotherapy + VEGFR-TKI is the preferred first-line treatment, based on improvements in PFS in this subgroup, when compared to sunitinib monotherapy. Although none of the studies have yet to show statistically significant improvements in OS, events have been few and further followup is needed. Targeted therapy can be considered an alternative active treatment option, primarily for patients who have a contraindication to immunotherapy.
– Active surveillance can also be considered in selected patients with favorable-risk/intermediate-risk with one risk factor, as some patients have slow-growing, low-volume, and/or asymptomatic disease or significant comorbidities.
– For IMDC intermediate- or poor-risk patients, either ipilimumab + nivolumab OR a combination of immunotherapy + VEGFR-TKI are the preferred first-line therapies. Targeted therapy remains an alternative option, primarily for patients who have a contraindication to immunotherapy or who are felt to be unable to tolerate combination therapy.

2.1.1.1. Risk-stratification

Risk-stratification is a critical first step in therapeutic decision-making for patients with mRCC. Using data from the targeted-therapy era, Heng and colleagues published a risk-stratification score based on information obtained from the IMDC. 51 Although mRCC has entered the immune checkpoint inhibitor era, the set of six IMDC criteria (hemoglobin less than the lower limit of normal, corrected calcium greater than the upper limit of normal (ULN), platelets greater than the ULN, neutrophils greater than the ULN, Karnofsky performance status less than 80%, and time from diagnosis to treatment of less than one year) remains the recommended tool for patient counselling, treatment selection (e.g., initial observation, systemic therapy, cytoreductive nephrectomy), and future research studies. These IMDC criteria stratify patients with mRCC into 3 risk groups based on their score: favorable (0), intermediate (1–2), or poor (3–6). It should be emphasized that the IMDC classification is a prognostic classification and not a predictive tool. To date, no reliable or helpful predictive biomarkers exist to inform optimal treatment selection.

2.1.1.2. IMDC favorable-risk

2.1.1.2.1. preferred therapies, 2.1.1.2.1.1. pembrolizumab + axitinib.

The KEYNOTE-426 study was a randomized, open-label, phase 3 study that assessed the efficacy and safety of pembrolizumab (200 mg IV every three weeks for up to 35 cycles) + axitinib (5 mg orally twice daily) vs. sunitinib (50 mg orally daily, four weeks per six-week cycle) as first-line therapy for mRCC. 9 The 861 patients (30% favorable-, 56% intermediate-, 13% poor-risk) enrolled in this study had clear-cell mRCC and no previous systemic therapy for mRCC. Patients were randomized 1:1 to pembrolizumab + axitinib (n=432) or sunitinib (n=429) with stratification based on IMDC risk group. Dual primary endpoints were OS and PFS in the overall population, while objective response rate (ORR) was the key secondary endpoint.

An update of extended followup results was recently published. 11 For the intention-to-treat (ITT) population, after a median followup of 30.6 months, pembrolizumab + axitinib significantly improved PFS compared to sunitinib, with medians of 15.4 months and 11.1 months, respectively (HR 0.71, 95% CI 0.60–0.84, p<0.0001). OS improvement was confirmed, as median OS had not been reached for pembrolizumab + axitinib, while median survival for sunitinib was 35.7 months (HR 0.68, 95% CI 0.55–0.85, p=0.0003). Pembrolizumab + axitinib demonstrated improved ORR (60% vs. 40%, p<0.0001). Complete response (CR) rate for pembrolizumab + axitinib was 9%.

In a prespecified subgroup analysis, there was a trend for improved PFS and OS with pembrolizumab + axitinib in patients with IMDC favorable-risk (n=269), which was not statistically significant (HR 0.79, 95% CI 0.57–1.09; and HR 1.06, 95% CI 0.60–1.86; respectively). In post-hoc analysis, objective response rate was 70% with pembrolizumab + axitinib vs. 50% with sunitinib. As noted by the authors of this study, the biology of this subgroup is often more indolent and the number of events to date is small. Furthermore, the study was not designed or adequately powered to detect differences between IMDC risk categories.

2.1.1.2.1.2. Nivolumab + cabozantinib

The CheckMate 9ER study was a randomized, open-label, phase 3 study that assessed the efficacy and safety of nivolumab + cabozantinib (a dual VEGFR/MET and AXL inhibitor) vs. sunitinib as first-line therapy for mRCC. 12 The 651 patients (22% favorable-, 58% intermediate-, 20% poor-risk) enrolled in this study had clear-cell mRCC (including sarcomatoid features), no previous systemic therapy for mRCC, and any IMDC risk group. Patients were randomized 1:1 to nivolumab (240 mg IV every two weeks for up to two years) + cabozantanib (40 mg orally daily) (n=323) or sunitinib (n=328). Randomization was stratified by IMDC risk group, tumor PD-L1 expression, and geographic region. Primary endpoints were PFS per blinded independent central review (BICR) in the overall population, while OS, ORR per BICR, and safety were the key secondary endpoints. The results of this study were recently published, with a median study followup of 18.1 months for OS. PFS was 16.6 months for nivolumab + cabozantinib and 8.3 months for sunitinib (HR 0.51, 95% CI, 0.41–0.64, p<0.001) in the ITT population. Median OS was not reached for either arm, however, HR was 0.60 (99% CI 0.40–0.89, p=0.001) in the ITT population. ORR by BICR was 55.7% vs. 27.1% favoring the nivolumab + cabozantinib arm (p<0.001). Improvements in PFS, OS, and ORR with nivolumab + cabozantanib were consistent across subgroups, including IMDC risk, tumor PD-L1 expression, and presence of bone metastases. In the favorable-IMDC risk group, HR for PFS by BICR and OS were 0.62 (0.38–1.01) and 0.84 (0.35–1.97), respectively. The CR rate for nivolumab + cabozantinib was 8%.

2.1.1.2.1.3. Lenvatinib + pembrolizumab

The CLEAR study was a randomized, open-label, phase 3 study, that assessed the efficacy and safety of the two drug combinations of lenvatinib + pembrolizumab or lenvatinib + everolimus (mTOR inhibitor) compared to sunitinib as therapy in advanced RCC. 13 , 14 The 1069 patients (33% favorable-, 55% intermediate-, 10% poor-risk) enrolled in this study had clear-cell mRCC (including sarcomatoid features), no previous systemic therapy for mRCC, and any IMDC risk group. Patients were randomized (1:1:1) to receive either lenvatinib (20 mg orally daily) + pembrolizumab (200 mg IV every three weeks for up to 35 cycles) (n=355), lenvatinib (18 mg orally daily) + everolimus (5 mg orally daily) (n=357) or sunitinib (n=357). The primary endpoint of the study was PFS by independent review committee. OS, ORR as assessed by an independent review committee, safety, and PFS as assessed by investigators were secondary endpoints.

After a median followup of 26.6 months, the PFS by independent review committee was longer with lenvatinib + pembrolizumab (23.9 months) compared to sunitinib (9.2 months) (HR 0.39, 95% CI 0.32–0.49, p<0.001) and also improved with lenvatinib + everolimus (14.7 months) compared to sunitinib (9.2 months) (HR 0.65, 95% CI 0.53–0.80, p<0.001) in the ITT group. PFS by investigator was also longer in the lenvatinib + pembrolizumab arm (22 months vs. 9.5 months, HR 0.47) and lenvatinib + everolimus arm (14.6 months vs. 9.5 months, HR 0.7) vs. sunitinib. Median OS was not reached in any of the three arms, however, the HR of 0.66 was statistically significant for only the lenvatinib + pembrolizumab (95% CI 0.49–0.9, p<0.001) arm compared to sunitinib. ORR and CR rate were 71.0% and 16.1% with lenvatinib + pembrolizumab, 53.5% and 9.8% with lenvatinib + everolimus, and 36.1% and 4.2% with sunitinib, respectfully.

On subgroup analysis, PFS and OS with lenvatinib + pembrolizumab were improved in all IMDC subgroups, with the exception of OS for the favorable group.

2.1.1.2.2. Other options: Sunitinib, pazopanib, or active surveillance

In a pivotal phase 3 trial, oral sunitinib produced higher response rates, improved quality of life, and resulted in longer PFS and OS than interferon-alfa in patients with metastatic clear-cell RCC. 52 , 53

The dose and schedule of sunitinib should be individualized for each patient to derive the optimal benefit. 54 It is still recommended to start with the monograph standard of four weeks on at 50 mg per day per six-week cycle. After evaluation of type and timing of toxicities, patients may require adjustments to the schedule and/or dose. Bjarnason and colleagues published a single-institution, retrospective review of patients treated with alternate dose and schedule of sunitinib compared to product monograph-recommended dosing; they found improved PFS and OS compared to the standard dosing group. 54 A prospective clinical trial conducted across Canada examined the same individualized dose titration scheme among 117 patients with metastatic clear-cell RCC. 55 Subjects in this study were started on sunitinib 50 mg/day with the aim to treat for 28 days. Standard treatment breaks of 14 days were reduced to seven days. Sunitinib dose and the number of days on therapy were individualized based on toxicity (aiming for ≤grade II toxicity with dose-escalation in patients with minimal toxicity). Individualized sunitinib therapy proved to be a safe and effective method to manage toxicity, with one of the best efficacies seen for oral VEGFR-TKIs in mRCC and no decline in quality-of-life scores during therapy. The median PFS observed in this study was 12.5 months, which significantly exceeded the expected 8.5 months based on a study with similar eligibility criteria. 55 In addition, toxicity appeared substantially less than on the traditional 50 mg/day, four-week on/two-week off schedule.

Based on phase 3 trial data, oral pazopanib produces an improvement in PFS compared to placebo in both cytokine-naive and refractory patients. 56 As first-line therapy, pazopanib (800 mg orally daily) has also been shown to be non-inferior to sunitinib with respect to PFS in the phase 3 COMPARZ clinical trial. 57 Toxicity profiles were different, with sunitinib-treated patients experiencing more fatigue, hand-foot syndrome, and thrombocytopenia, whereas pazopanib-treated patients experiencing more elevations in hepatic transaminases. 57

A post-hoc analysis of the COMPARZ trial found that for patients without vs. with adverse event (AE)-related dose reductions, median PFS, median OS, and ORR were 7.3 vs. 12.5 months, 21.7 vs. 36.8 months, and 22% vs. 42% (all p<0.0001) for pazopanib, and 5.5 vs. 13.8 months, 18.1 vs. 38.0 months, and 16% vs. 34% (all p<0.0001) for sunitinib, respectively. The improved outcomes were similar for patients needing dose interruptions for toxicity. Dose modifications or interruptions, when required because of AEs, were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients for both sunitinib and pazopanib. 58

As outlined above, the results of the CLEAR study showed improved PFS by both independent review and by investigator review for lenvatinib + everolimus compared to sunitinib. However, there is no OS benefit as yet observed at 26.6-month followup, with a HR of 1.15 (95% CI 0.88–1.50, p=0.30). Most participants felt that further maturity of the data was required to potentially recommend this as a first-line treatment and, at this time, lenvatinib + everolimus could not be recommended as a first-line option. 13 , 14

In the opinion of the participants at the consensus meeting, an initial period of observation (active surveillance) also remains a reasonable option in select patients, given that all available treatments can be associated with side effects, and that some patients may experience an indolent clinical course with stable or slow-growing, low-volume, and/or asymptomatic metastases or in patients with competing risks from other comorbidities. This is supported by prospective, observational data presented by Rini and colleagues. 59 (Refer to section 2.5 regarding management of oligometastases.)

High-dose interleukin (IL) 2 continues to be used in the province of Quebec because of its potential to induce durable, long-term remissions in a small subset of fit patients with advanced RCC. 60 High does IL-2 should only be used by experienced physicians in centers with resources to manage severe acute toxicities. For the most part, this immunotherapy approach has been replaced with the use of newer immune checkpoint inhibitors.

2.1.1.3. IMDC intermediate- or poor-risk

2.1.1.3.1. preferred therapies, 2.1.1.3.1.1. ipilimumab + nivolumab.

The CheckMate 214 study was a randomized, open-label, phase 3 trial of ipilimumab (3 mg/kg IV every three weeks for four cycles) + nivolumab (1 mg/kg IV every three weeks for four cycles) followed by nivolumab monotherapy (3 mg/kg IV every two weeks) vs. sunitinib. 8 The 1096 subjects enrolled in the trial were ≥ 18 years of age with previously untreated advanced RCC with a clear-cell component. They were randomized to either ipilimumab + nivolumab (n=550) or sunitinib (n=546). As per inclusion criteria, most enrolled patients had IMDC intermediate- (n=425) or poor-risk disease (n=422). The co-primary endpoints were OS, ORR, and PFS in intermediate- and poor-risk patients. The same endpoints were used for the exploratory cohort of favorable-risk patients. 61

An update of this trial was presented at ESMO 2020 and the ipilimumab + nivolumab arm continues to show improvement in all three co-primary endpoints at four years of followup. 10 , 62 In the intermediate- or poor-risk group, median OS was 48.1 months for the ipilimumab + nivolumab compared to 26.6 months for sunitinib (HR 0.65, 95% CI 0.54–0.78). Median PFS was 11.2 months for ipilimumab + nivolumab compared to 8.3 months for sunitinib (HR 0.74, 95% CI 0.62–0.88). PFS curves appear to have plateaued after 30 months, with a PFS rate of approximately 35% at five years following treatment with ipilimumab + nivolumab. CR rate was 10.4% with ipilimumab + nivolumab. Among favorable-risk patients, no significant difference was demonstrated between the treatment arms for OS or PFS (HR 0.93 and 1.84, respectively). Median duration of response has not been reached for ipilimumab + nivolumab responders, and approximately 45% of responding patients remain in remission without any active therapy.

2.1.1.3.1.2. Pembrolizumab + axitinib

The phase 3 study, KEYNOTE-426, evaluated its dual primary endpoints of OS and PFS in the unselected overall population, including patients with favorable-risk (n=269) and intermediate-/ poor-risk (n=592). 9 , 11 The overall data are reported above. With respect to IMDC risk groups, at a median followup of 30.6 months, prespecified subgroup analysis showed that pembrolizumab + axitinib was associated with an OS and PFS improvement in intermediate- or poor-risk disease (HR 0.63, 95% CI 0.50–0.81, p=0.0001; and HR 0.69, 95% CI 0.56– 0.84, p=0.0002; respectively). Median duration of response was reached with 23.5 months for pembrolizumab + axitinib vs. 15.9 months in the sunitinib group.

2.1.1.3.1.3. Nivolumab + cabozantinib

PFS by BICR was the primary endpoint for the CheckMate 9ER phase 3 clinical trial, while OS was a secondary endpoint. 12 The unselected population included patients with favorable- (n=146), intermediate- (n=376) and poor-risk (n=129) disease. The overall data are reported above. There was improved PFS and OS in the nivolumab + cabozantinib arm for intermediate- (HR 0.54 and 0.70) and poor-risk groups (HR 0.37 and 0.37), respectively. Median duration of response was 20.2 months with nivolumab + cabozantinib vs. 11.5 months with sunitinib.

2.1.1.3.1.4. Pembrolizumab + lenvatinib

The primary endpoint for the phase 3 CLEAR study was PFS by independent review committee. OS was a secondary endpoint. The unselected population included patients with favorable- (n=291), intermediate- (n=682) and poor-risk (n=96) disease. The overall data are reported above. 13 , 14

On subgroup analysis, there was improved PFS and OS in the lenvatinib + pembrolizumab arm for IMDC intermediate- (HR 0.44 and 0.72) and poor-risk groups (HR 0.18 and 0.30), respectively, vs. sunitinib. 13

2.1.1.3.2. Other options

The recommendation that sunitinib or pazopanib are possible but non-preferred options in the upfront setting for intermediate- or poor-risk, come from the same data sets as described above in the favorable-risk setting; intermediate- and poor-risk patients were treated with VEGFR-TKI therapy in pivotal trials as well. The consensus was that sunitinib and pazopanib would still be preferentially used in patients with contraindications for immunotherapy or who are felt to be unable to tolerate combination therapy.

In the CLEAR study, 13 the lenvatinib + everolimus arm showed improved PFS for IMDC intermediate- (HR 0.67) and poor-risk patients (HR 0.73). However, no improvement in OS has been demonstrated for any of the IMDC subgroups. As noted previously, further maturity of data is required and this drug combination is not currently recommended for first-line treatment.

2.1.1.3.2.1. Avelumab + axitinib

JAVELIN Renal 101 was a phase 3, randomized, open-label study comparing avelumab (10 mg/kg IV every two weeks) + axitinib (5 mg orally twice daily) to sunitinib among 886 patients with clear-cell advanced RCC and no prior systemic therapy. 63 All prognostic risk groups were included. The co-primary endpoints were PFS and OS among patients with PD-L1-positive tumors (n=560) as defined by ≥ 1% of immune cells staining positive within the tumor area of the tested tissue sample using the SP263 assay (Ventana). Secondary endpoints were OS and PFS in the overall population. The updated results after minimum followup of 13 months have been published. 64 In the PD-L1+ group, median PFS was 13.8 months with avelumab + axitinib vs. 7.0 months with sunitinib (HR 0.62, 95% CI 0.490–0.7777, one-sided p<0.001). In the ITT population, the median PFS was 13.3 months with avelumab + axitinib vs. 8.0 months with sunitinib (HR 0.69, 95% CI 0.574–0.825, one-sided p<0.001). OS data for this study were immature at the data cutoff, with a suggestion of benefit for avelumab + axitinib, but no statistical significance to date (PD-L1 + population: HR 0.828, 95% CI 0.596–1.151, p=0.1301; and overall population: HR 0.796, 95% CI 0.616–1.027, p=0.0392). At this time, the majority of the participants in the 2020 consensus meeting recommended keeping avelumab + axitinib in the “other options” section for first-line therapy pending final analysis for OS. It was noted that other VEGFR-TKI + immunotherapy combinations have demonstrated survival benefit and are, therefore, preferred options.

Axitinib is currently only approved in Canada as monotherapy after failure of prior systemic therapy with either a cytokine or sunitinib, or in combination with pembrolizumab as first-line treatment for mRCC. Avelumab is not currently approved in Canada for mRCC (although it has indications for other malignancies).

2.1.1.3.2.2. Cabozantinib

The randomized, phase 2 CABOSUN trial compared cabozantinib (60 mg orally daily) to sunitinib first-line. 65 This small, investigator-initiated trial (n=157) had 81% intermediate- and 19% poor-risk patients and demonstrated a significant improvement in PFS in favor of cabozantinib. In unplanned analyses, it showed particularly promising activity in patients with bone metastases, although this was a very small subset of patients. It should be noted that the sunitinib arm median PFS was significantly shorter than expected partly because 23% of the patients in the sunitinib arm were not evaluable for response vs. 8% in the cabozantinib arm.

Health Canada approved the use of cabozantinib as first-line treatment in patients with intermediate- and poor-risk advanced RCC. Although consensus was not reached, some of the participants in the 2020 consensus meeting felt that cabozantinib may be an option for intermediate-/poor-risk patients who are not ideal candidates for immunotherapy.

2.1.2. Second-line and later therapy options

2.1.2.1. progression on or intolerance to first-line immune checkpoint inhibitor-based regimen.

– For patients who progress on, or who are intolerant of first-line immune checkpoint inhibitors, there is no prospective, randomized, phase 3 evidence available to select a preferred treatment option; options for patients in this situation include sunitinib, pazopanib, axitinib, cabozantinib, or lenvatinib + everolimus.

For those individuals who progress on a regimen that includes an immune checkpoint inhibitor, there are no data yet available to guide the selection of subsequent therapy. Several retrospective reviews show that VEGFR-TKIs have activity after immunotherapy.

The only prospective study in this setting has demonstrated the activity of axitinib after immunotherapy; therefore, axitinib may be a preferred option post-immunotherapy progression. 66 Seventy-four percent of patients had received two or more therapies prior to axitinib. In this study, axitinib (initial starting dose 5 mg orally twice daily) was given on an individualized schedule, with significant inter-individual variation in the optimal dose and schedule, as has been shown for sunitinib. The authors suggested that individualized dosing of axitinib should be considered, given in combination with immunotherapy.

Based a subgroup analysis of the METEOR study, cabozantinib is also a preferred option post-immunotherapy progression, particularly after VEGFR-TKI + immunotherapy combination. 67

We await the results of more prospective studies in the post-immunotherapy setting to provide information about best practices in this space.

Currently, the selection of a VEGFR-TKI-targeted therapy that is among the recommended first-line options (i.e., sunitinib, pazopanib) is a reasonable choice. Based on their evidence of activity in the first- or second-line setting, other options include axitinib, cabozantinib, and lenvatinib + everolimus.

2.1.2.2. Progression on or intolerance to first-line sunitinib or pazopanib

– For patients who are intolerant to sunitinib or pazopanib, switching to the other VEGFR-TKI is a reasonable choice.
– For patients who progress on first-line sunitinib or pazopanib, preferred options are nivolumab or cabozantinib.
– Other evidence-based options are lenvatinib + everolimus (based on a small phase 2 study demonstrating a PFS advantage over everolimus monotherapy) or everolimus monotherapy (although found to be inferior to alternatives such as nivolumab and cabozantinib).

2.1.2.2.1. Intolerance to first-line VEGFR-TKI-targeted therapy

If patients stop first-line therapy due to toxicity and not progression, another first-line therapy is very reasonable to try. Data from the IMDC suggest the outcomes when therapies are switched due to toxicity and not progression are better than would be seen as second-line therapy after progression. 68

2.1.2.2.2. Progression on first-line VEGFR-TKI-targeted therapy: Preferred options

2.1.2.2.2.1. nivolumab.

In the phase 3 CheckMate 025 trial, intravenous nivolumab (3 mg/kg IV every two weeks) produced better response rates and a significantly longer OS compared to oral everolimus (10 mg orally daily) in patients who had failed one or two previous lines of systemic therapy regardless of the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score or number of previous antiangiogenic therapies. 69 Benefit was observed irrespective of PD-L1 expression. In addition, grade 3 or 4 treatment-related AEs and treatment-related AEs leading to discontinuation were less frequent with nivolumab than with everolimus. Quality-of-life outcomes increased over time in the nivolumab group and were significantly better than the everolimus group at each assessment point.

There is also data to support the use of nivolumab in the third-line setting. In the CheckMate 025 trial, 28% of randomized subjects had received two prior VEGFR-TKI-targeted therapies. 69 OS results suggest a benefit of nivolumab over everolimus in this setting.

The phenomena of pseudoprogression and delayed responses on immuno-oncology agents may make monitoring of efficacy challenging, but it should be noted this occurs in a small minority of patients. 70 , 71 Thus, treatment beyond progression should be restricted to patients showing clinical benefit, stability, or a mixed response.

2.1.2.2.2.2. Cabozantinib

The randomized, phase 3 METEOR trial compared cabozantinib to everolimus among patients previously treated with one or more prior VEGFR-TKIs. 67 A small minority of patients had also received a checkpoint inhibitor in addition to one or two TKIs. Cabozantinib demonstrated a significant improvement in PFS (primary endpoint), ORR, and OS in the overall population. 67 Approximately 30% of patients had received at least two prior VEGFR-TKI therapies; even in this subset, notable benefit in PFS and OS were observed in patients receiving cabozantinib compared to those receiving everolimus. Additional prior checkpoint blockade therapy did not appear to impact benefit and significant improvements in outcome were maintained in this small patient population.

2.1.2.2.3. Progression on first-line VEGFR-TKI-targeted therapy: Other options

2.1.2.2.3.1. axitinib.

Axitinib is listed as “other options” in VEGF-pretreated populations largely based on data from the phase 3 AXIS trial, in which axitinib demonstrated improved PFS, but no OS benefit compared to sorafenib as second-line therapy in patients progressing after first-line sunitinib. 72 However, in this study, axitinib was compared to a more arguably active agent, sorafenib, as opposed to the CheckMate 025 and METEOR studies, which were compared to less active everolimus. Further, there are patients in the CheckMate 025 and METEOR trials who went on to receive axitinib post-nivolumab or cabozantinib, respectively. Retrospective analyses suggest patients demonstrate benefit to VEGFR-TKIs in the third-line setting, inclusive of axitinib. 73 , 74

2.1.2.2.3.2. Lenvatinib + everolimus

A small, three-arm, randomized, phase 2 trial of oral lenvatinib, oral everolimus, and the combination of both demonstrated improved PFS for the combination arm over everolimus alone (median 14.6 months vs. 5.5 months; HR 0.40, 95% CI 0.24–0.68, p=0·0005). 75 The subjects were 153 patients who had progressed on VEGFR-TKI-targeted therapy and were randomized 1:1:1 to lenvatinib alone (24 mg daily), everolimus alone (10 mg daily), or the combination of lenvatinib (18 mg daily) and everolimus (5 mg daily).

2.1.2.2.3.3. Everolimus

In the phase 3 RECORD-1 trial, oral everolimus (mTOR inhibitor) produced a significantly longer PFS than placebo, with an acceptable toxicity profile in patients who had failed sunitinib or sorafenib or both. 76 In that trial, 25% of subjects randomized had received two prior VEGFR-TKI therapies and a significant improvement in PFS was seen in the everolimus arm vs. the placebo arm. It should be noted, however, that everolimus has been found to be inferior to several other therapies in subsequent randomized trials, including the phase 3 CHECKMATE 025 (nivolumab) and METEOR (cabozantinib), and the phase 2 study compared to lenvatinib + everolimus. 67 , 69 , 75

2.1.2.3. Progression on or intolerance to prior VEGFR-TKI AND prior immune checkpoint inhibitor

– For patients who progress on, or who are intolerant of, both prior VEGFR-TKI and prior immune checkpoint inhibitor, there is little evidence available to select a preferred treatment option; options for patients in this situation include any of the options that have not previously been tried among: sunitinib, pazopanib, axitinib, cabozantinib, or lenvatinib + everolimus.

There is a paucity of data on which to base treatment decisions in this space. In the absence of evidence-based recommendations, therapeutic options include any of the therapies mentioned in the above section with evidence in first- or subsequent-line therapy that have not yet been used for a particular patient. Cabozantinib may be a preferred option in this space based upon the METEOR study.

2.2. Non-clear-cell histology

– There is no standard therapy for advanced non-clear-cell RCC and enrollment in clinical trial is the preferred option. It is generally accepted that patients with non-clear-cell histology should be treated similarly to patients with clear-cell histology. Clinical trials support the use of immunotherapy in this setting (ipilimumab + nivolumab; pembrolizumab + axitinib; pembrolizumab monotherapy), cabozantinib, or sunitinib

In patients with metastatic or advanced RCC with non-clear-cell histology, enrollment in clinical trials should be encouraged whenever possible.

Two phase 2 trials randomized patients to everolimus vs. sunitinib as first-line therapy for non-clear-cell pathologies with crossover allowed at progression. The ESPN trial futility analysis resulted in early termination of the trial due to inferior PFS and OS for everolimus. 77 The ASPEN trial demonstrated sunitinib was superior to everolimus for PFS. 78

The results phase 2 KEYNOTE 427 study of first-line pembrolizumab monotherapy (200 mg IV every three weeks) in non-clear-cell RCC (cohort B) have been presented in abstract form. 79 (At 18 months, PFS rate was 18.9 months [range 9.9– 26.0 months] and OS 67%. Overall response rate was 26% [95% CI 19.5–33.5]; 10 CRs, 33 partial responses [PRs]).

The PAPMET phase 2, open-label study was designed to assess the role of MET kinase inhibitors compared to standard of care sunitinib in patients with advanced papillary RCC. This data was presented at the 2021 ASCO Genitourinary Cancers Symposium and concurrently published. 15 , 16 PFS was the primary endpoint. Initially, patients were randomized to one of four arms: cabozantinib, crizotinib, savolitinib, or sunitinib. The savolitinib (n=29) and crizotinib (n=28) arms were stopped to accrual after a prespecificied futility analysis, while planned accrual for both the cabozantinib (n=44) and sunitinib (n=46) arms were completed. PFS was longer in the cabozantinib arm (9.0 months) compared to the sunitinib arm (5.6 months), with HR 0.60 (0.37–0.97, one-sided p=0.019). There was no improvement in PFS with savolitinib or crizotinib compared to sunitinib. There were no differences in OS between all four treatment arms. Response rate for cabozantinib was 23% vs. 4% for sunitinib (two-sided p=0.010). 16

2.3. Sarcomatoid variant or poorly differentiated RCC ( Table 2 )

Options for patients with advanced metastatic sarcomatoid or poorly differentiated RCC

Participation in clinical trials is strongly encouraged

Therapy	Rationale
Ipilimumab + Nivolumab (preferred)	Based on subgroup analysis of sarcomatoid RCC patients in CheckMate 214 showing a complete response rate of 18% and a mOS of 31 months compared to sunitinib (CR 0% and mOS 13.6)
Axitinib + Pembrolizumab (preferred)	Based on subgroup analysis of sarcomatoid RCC patients in KEYNOTE 426 showing a complete response rate of 12% and improved mOS (not reached) compared to sunitinib (CR 0%)
Nivolumab + cabozantinib (preferred)	Based on subgroup analysis of sarcomatoid RCC in Checkmate 9ER showing improved PFS (10.9 m and mOS not reached compared to sunitinib (PFS 4.2 and mOS 19.7 m)
Sunitinib	Based on prospective, non-randomized data from the Expanded Access Program

CR: complete response; mOS: median overall survival; PFS: progression-free survival; RCC: renal cell carcinoma.

In patients with advanced or metastatic sarcomatoid or poorly differentiated RCC, strong preference is to use immunotherapy-based therapies. In patients who are not candidates for immunotherapy, sunitinib can be considered.

A post-hoc analysis of patients with sarcomatoid mRCC randomized to ipilimumab + nivolumab or sunitinib in the CheckMate 214 study suggests significant efficacy of ipilimumab + nivolumab compared to sunitinib. 80 The ORR was 56.7% for ipilimumab + nivolumab compared to 19.2% for sunitinib, with CR proportions of 18.3% vs. 0%. Median OS was 31.2 months compared to 13.6 months, again favoring ipilimumab + nivolumab (HR 0.55, 95% CI 0.33–0.90, p<0.0155). Rini and colleagues also presented a post-hoc analysis of similar patients, which showed an ORR rate of 59% compared to 31.5% with pembrolizumab + axitinib compared to sunitinib. 81 CR rate was 12% for the combination and 0% for sunitinib. PFS and OS were also improved.

The CheckMate 9ER phase 3 study of first-line treatment of advanced RCC included 75 (11.5%) patients with sarcomatoid features treated with either nivolumab + cabozantinib (n=34) vs. sunitinib (n=41). Results of 18.1-month followup, presented at the ASCO Genitourinary Symposium 2021, demonstrated an improved PFS and OS with nivolumab + cabozantinib compared to sunitinib (10.9 months vs. 4.2 months, HR 0.39 [95% CI 0.22–0.70]; and not reached vs. 19.7 months, HR 0.36 [95% CI 0.16–0.82]). ORR for nivolumab + cabozantinib was 55.9% vs. 22.0% with sunitinib. 82 Further data will be reported with additional followup.

Patients with sarcomatoid features were eligible for the CLEAR study (n=73, 7%), however, no separate analysis of this group has been presented. 13 , 14

2.4. Role of cytoreductive nephrectomy

○ Patients with a good performance status (Eastern Cooperative Oncology Group [ECOG] ≤ 1 or Karnofsky Performance Status [KPS] ≥80%), minimal symptoms related to metastases, a resectable primary tumor, and a limited burden of metastatic disease should be offered upfront cytoreductive nephrectomy followed by metastases-directed therapy, a period of surveillance, or systemic therapy.
○ Patients with significant systemic symptoms from metastatic disease, active central nervous system metastases, a limited burden of disease within the kidney relative to the cumulative extra-renal volume of metastases, rapidly progressing disease, a poor performance status (ECOG >1 or KPS <80%), and/or limited life expectancy should not undergo upfront cytoreductive nephrectomy.
– Patients with mRCC who don’t fall within the two above categories should be offered initial treatment with systemic therapy, with consideration of deferred cytoreductive nephrectomy given to those with a significant and stable clinical response.

The recommendations for cytoreductive nephrectomy come from a recent KCRNC consensus statement by Mason and colleagues. 83 These recommendations were based largely on two randomized, controlled studies published in 2018: CARMENA and SURTIME. 84 , 85 It should be noted that these key pieces of evidence regarding cytoreductive nephrectomy and systemic therapy are both from the VEGF-targeted era. To what extent these are applicable in the era of immune checkpoint inhibition has yet to be investigated.

Based on the ESMO 2020 update of the Checkmate 214 study of ipilimumab + nivolumab vs. sunitinib, in a small subgroup of patients with renal tumor in situ (53 patients), ORR to ipilimumab + nivolumab was 35% in the primary tumor. However, the median OS was inferior in this subgroup for both the ipilimumab + nivolumab (26.1 months) and sunitinib (14.3 months) arms. No CRs were observed in patients with the primary renal lesion in situ. 62

Exploratory subgroup analysis of patients from Keynote-426 by prior nephrectomy was presented at the International Kidney Cancer Symposium 2020. Pembrolizumab + axitinb showed OS, PFS, and ORR benefit relative to sunitinib as first-line therapy in mRCC patients who underwent prior nephrectomy (n=718) and those who did not undergo prior nephrectomy (n=143). 86

In terms of alternate forms of cytoreduction, the ongoing, randomized, phase 2 CYTOSHRINK trial (n=78) is evaluating the role of cytoreductive stereotactic body radiation therapy (SBRT) to the renal primary plus ipilimumab + nivolumab vs. ipilimumab + nivolumab alone for patients with de novo mRCC and IMDC intermediate- or poor-risk disease. 87

2.5 Role of local therapy in oligometastases

– In select patients with a limited number of sites of metastatic disease and stable clinical condition, local therapy, such as resection and/or SBRT, to treat all sites of metastatic disease may be a reasonable option.

2.5.1. Metastasectomy

There are no randomized trials showing the benefit of metastasectomy in RCC with oligometastatic disease. However, among patients with metachronous metastases after nephrectomy, about one-third are eligible for metastasectomy and several large cohorts report 50% five-year survival following complete resection of metastases. 88 , 89 Based on available observational data, patients most likely to benefit from metastasectomy are those diagnosed with metastases after at least a two-year DFS, those with isolated metastases, and those with surgically favorable metastatic locations (e.g., lung, thyroid, and adrenal). 90 A period of observation is reasonable to confirm that the metastatic disease is not rapidly progressing. In addition, patients on systemic therapy should be re-evaluated during their course of disease for the option of metastasectomy to render them no evidence of disease (NED) either due to favorable response or oligoprogression (see section 2.6). There is no defined role for “pseudoadjuvant” systemic therapy after metastasectomy if a patient is rendered NED.

2.5.2. SBRT

SBRT is another option for oligometastases. Unlike conventional radiotherapy, SBRT involves delivery of very conformal, ultra-hypofractionated radiation over 1–5 fractions, where the goal is to eradicate or provide long-term local control of the treated tumor(s). In patients with medically inoperable, early-stage RCC, SBRT to the primary tumor results in very high local control rates. 91 , 92 Similar high local control rates of approximately 90% are observed when using SBRT to treat RCC metastases in various body sites (thoracic, abdominal, soft tissue, bone, brain). 93 , 94 Such data refutes the previously held notion that RCC is radio-resistant.

Thus, SBRT can be an alternative to surgical metastasectomy in patients who are inoperable or whose tumor(s) are not easily resectable without morbidity. It can also be complimentary to surgical resection when there are multiple metastases where a combined approach can be considered to spare patients multiple surgical procedures.

2.6. Role of local therapy in oligoprogression

– Local therapy may be considered in the setting of oligoprogression.

There are no randomized trials for the management of metastatic RCC patients with sites of oligoprogression.

A Canadian phase 2 trial of using SBRT in 37 mRCC patients with oligoprogression while on sunitinib or pazopanib has been reported in abstract form. 95 At a median followup of 11.6 (1.8–53.5) months, the median PFS from study entry was 9.6 months (95% CI 7.4–20.5), with the vast majority of progression occurring outside of the irradiated areas. The two-year local control of the irradiated tumors was 96%. The two-year OS from study entry was 77%. The cumulative incidence of changing systemic therapy was 47% at one year and 75% at two years, with a median time to a change in systemic therapy of 12.6 months, thus essentially prolonging the PFS for the TKI.

Treatment with local therapy (surgery, SBRT, cryotherapy, and/or radiofrequency ablation [RFA]) can be considered, with the goal of delaying the need to start or change systemic therapy. Such an approach has previously been studied primarily in metastatic non-small-cell lung cancer patients who developed oligoprogression while on TKIs. 95

2.7. Role of radiation therapy in symptom control

– Radiation therapy may be considered to palliate symptoms from the primary tumor or metastases lesions.

RCC is not a radio-resistant tumor and many patients can achieve palliation of symptoms related to their cancer through radiation therapy (RT). New radiation techniques, such as stereotactic RT, may improve outcomes compared to traditional external beam RT; several ongoing trials are in progress. 96 Clinical trials involving RT should be supported.

2.8. Role of bone-modifying agents for patients with skeletal metastases

– Bone-modifying agents can be considered for patients with bone metastases to decrease skeletal-related events (SRE).

About one-third of patients with metastatic RCC will develop bone metastases, which can lead to an SRE as part of their disease. 97 Currently available bone-modifying agents have been shown to reduce SREs in this population.

In a phase 3 trial of zoledronic acid (ZA) vs. placebo, a subset analysis of 74 mRCC patients showed that administration of ZA compared to placebo resulted in a significant decrease in SREs in the ZA group. 98 , 99 Thus, monthly administration of ZA is a reasonable option. Careful monitoring of renal function is required.

Denosumab is an inhibitor of the receptor activator of nuclear factor kappa-B (RANK) ligand. In a phase 3 trial of denosumab vs. ZA for treatment of malignancy with bone metastases (excluding breast or prostate cancer patients), a subset of patients enrolled in this trial had mRCC. 100 This trial demonstrated non-inferiority for denosumab compared to ZA in terms of SRE reduction for the group overall, although no subgroup analysis for RCC patients was done. Thus, denosumab could also be considered a reasonable option for this population of patients, particularly those with impaired renal function obviating bisphosphonate use.

Patients receiving bone-modifying agents are at risk of hypocalcemia, therefore, calcium and vitamin D supplements are recommended. However, paraneoplastic hypercalcemia can also occur in RCC, so monitoring of serum calcium levels is important regardless. Patients starting on any bone-targeted therapy should ensure they have had a thorough dental history and recent dental examination prior to starting therapy, given the risk for developing osteonecrosis of the jaw (ONJ). Patients should also be monitored for this throughout the course of their therapy, as there a higher incidence (10%) for ONJ in combination with VEGFR-TKIs. 101

2.9. Patient and caregiver issues

– Patients should be provided access to multidisciplinary care, including kidney cancer specialists and health professionals with expertise in supportive care.
– Information should be provided to patients and caregivers on community resources. Patients and caregivers should be encouraged to contact and/or join Cancer du rein Canada/Kidney Cancer Canada ( www.kidney-cancercanada.ca ).
– Screening of patients for hereditary kidney cancer risk, including appropriate genetic testing, should be the standard of care, as outlined in the Canadian guideline on genetic screening for hereditary renal cell cancers.
– Patient enrolment in the Canadian Kidney Cancer information system (CKCis) database is strongly encouraged.

Patient care should involve a multidisciplinary team with expertise in the management of RCC, which may involve communication with and/or referral to another center.

All patients and caregivers should be referred to a reputable patient group for information and support, such as Kidney Cancer Canada 102 and the Canadian Cancer Society. 103 These groups provide accurate information that has been expertly reviewed and presented in a format that is easy for patients to understand. They also provide support to help patients and caregivers cope with a cancer diagnosis. Patients and caregivers should be asked at visits if they are connected to a patient group and have the information and support they need.

While a minority of patients have hereditary RCC, every patient should be screened for hereditary RCC risk using the Canadian guideline that includes risk factors such as first- or second-degree relative with renal tumor, young age (<45 years old), bilateral disease, uncommon histology, and associated hereditary conditions. 104

To facilitate clinical and basic research in kidney cancer in Canada, the web-based CKCis national registry was developed in 2009. To date, this registry includes 13 000 patients diagnosed with kidney cancer from 14 academic centers across Canada. Voluntary patient enrollment is strongly encouraged.

Advanced RCC has seen many treatment advances in the past several years, with the introduction of many novel therapies. Recent evidence from the KEYNOTE 426 and CheckMate 214 studies, and now the addition of the CheckMate 9ER and CLEAR studies, has mandated a rearrangement of treatment algorithms for advanced clear-cell RCC with the use of doublet immunotherapy or immunotherapy in combination VEGFR-TKI. We now await both clinical experience, prospective clinical trials, and development of predictive biomarkers to help inform the optimal choice and sequence of currently available treatment options.

In absence of head-to-head comparison between combination approaches at this time, therapy should be individualized based on patient profiles and disease characteristics, and each agent chosen should be optimized to obtain the best results, with multidisciplinary care being paramount in achieving maximal benefit for patients.

Ongoing participation in research and clinical trials to further our knowledge in this field continues to be an essential priority for healthcare professionals with an interest in advanced RCC.

Acknowledgements

The authors would like to thank Dr. Michael Atkins, from the Georgetown Lombardi Cancer Centre Washington, DC, who was visiting speaker at the 11 th Canadian Kidney Cancer Forum (CKCF) and participated in the consensus meeting. They would also like to thank the Kidney Cancer Research Network of Canada (KCRNC).

The following is a consensus report from the Kidney Cancer Research Network of Canada (KCRNC), with an update from the 11th Canadian Kidney Cancer Forum, held virtually on October 16, 2020, and subsequent discussions and updates after the ASCO Genitourinary Cancers Symposium, held in February 2021.

Prior to publication, this consensus statement was reviewed and approved by the CUA Guidelines Committee.

Competing interests: Dr. Canil has participated in advisory boards for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Roche, and Sanofi Genzyme; is a speaker for Bayer; has received travel grants from Amgen, Sanofi Genzyme, and Pfizer; has received research funding from Janssen; and has participated in clinical trials supported by AstraZeneca, Eisai, Janssen, and Roche. Dr. Kapoor is an advisory board beer for Amgen, BMS, Eisai, Ipsen, Merck, Novartis, Pfizer, Roche, and Verity; has received grants and/or honoraria from Amgen, Novartis, and Pfizer; and has participated in clinical trials supported by Amgen, BMS, CCTG, Merck, Novartis, and Pfizer. Dr. Basappa has received honoraria from Astellas Pharma, Eisai, Ipsen, Janssen, Merck, and Pfizer; has had a consulting or advisory role with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Pfizer, and Roche Canada; and has received travel, accommodations, and expenses from Eisai and Janssen. Dr. Bjarnason has been an advisory board member for, has received speaker honoraria from; and has participated in clinical trials supported by Ipsen, MBS, Merck, and Pfizer; and owns stock in Abbott and Pfizer. Dr. Bossé has received honoraria from Amgen, AstraZeneca, Ipsen, and Janssen; has had a consulting or advisory role with Abbvie, Bayer, Bristol-Myers Squibb, Ipsen, and Pfizer; and has received research funding from AstraZeneca. Dr. Gray has participated in advisory boards for Bayer, Merck, Novartis and Roche; has received speaker honoraria from Janssen and Sanofi; and has participated in clinical trials supported by Astellas and BMS. Dr. Heng has been an advisor for Astellas, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, and Pfizer; and has received research funding from BMS, Exelixis, Ipsen, Novartis, and Pfizer. Dr. Kollmannsberger has participated in advisory boards for Astellas, BMS, Eisai, EMD Serono, Ipsen, Janssen, Merck, Pfizer, and Roche; has received speaker honoraria from Astellas, BMS, Eisai, Ipsen, Janssen, Merck, Pfizer, and Roche; and has participated in clinical trials supported by Astellas, BMS, Eisai, EMD Serono, Ipsen, Janssen, Merck, Pfizer, and Roche. Dr. Lalani has received honoraria from AbbVie, Astellas, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera; and research funding from EMD Serrono, Ipsen, Novartis, and Roche. Dr. North has received honoraria from Astellas Pharma, Janssen-Ortho, Merck, Novartis, Pfizer, Roche Canada, and Sanofi Canada; has had a consulting or advisory role with Astellas Pharma, AstraZeneca, Janssen Oncology, Merck, Novartis, Pfizer, Roche Canada, and Sanofi Canada; has received research funding from Astellas Pharma (Inst), AstraZeneca (Inst), Janssen (Inst), Novartis Canada Pharmaceuticals Inc. (Inst), Roche Canada (Inst), and Sanofi Canada (Inst); and has received travel, accommodations, and expenses from AstraZeneca. Dr. Soulieres has been an advisory board member for Bayer, BMS, Merck, and Novartis; has received honoraria from BMS, Merck, and Pfizer; and has participated in clinical trials supported by BMS, Merck, Novartis, and Pfizer. Dr. Winquist has received grants and/honoraria from Amgen, Bayer, Eisai, Merck, and Roche; and has participated in clinical trials supported by AstraZeneca, BMS, Eisai, Merck, and Pfizer. Dr. Wood has received research funding from Aragon Pharmaceuticals (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Exelixis (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), and Roche Canada (Inst). Dr. Hotte has been an advisory board member for, received honoraria from and participated in clinical trials supported by Astellas, Bayer, and Janssen. The remaining authors report no competing personal or financial interests related to this work.

To answer the multiple-choice questions associated with this article, go to: www.cuasection3credits.org/cuajapril2021 . This program is an Accredited Self-Assess-ment Program (Section 3) as defined by the Maintenance of Certification Program of The Royal College of Physicians & Surgeons of Canada, and approved by the Canadian Urological Association. Remember to visit MAINPORT ( www.mainport.org/mainport/ ) to record your learning and outcomes. You may claim a maximum of 1 hour of credit.

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Updated NCCN Kidney Cancer Guidelines Bring New Recommendations for Advanced Non–Clear Cell RCC

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Bradley McGregor, MD, shared his insights on the updated NCCN Clinical Practice Guidelines in kidney cancer.

Bradley McGregor, MD

The changes in the 2024 update to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the treatment of patients with kidney cancer include new recommendations for the treatment of those with advanced non–clear cell renal cell carcinoma (RCC), and future research and data could help inform more specific recommendations based on the subtype of disease within this histology, according to Bradley McGregor, MD.

In the updated guidelines, the combinations of lenvatinib (Lenvima) and pembrolizumab (Keytruda), as well as cabozantinib (Cabometyx) plus nivolumab (Opdivo), were moved to preferred regimens for those with metastatic stage IV or relapsed non–clear cell RCC. 1 Other preferred recommendations for this subtype include cabozantinib monotherapy and clinical trials.

“In the future, we would like to break down [these recommendations] a little bit further. Hopefully, we will be able to think about not just histology but also genomics to try to pin down what therapy works best for each disease type. We have a lot of work to get there, but we're taking steps forward with each year that goes by,” said McGregor, who is a senior physician, the director of Clinical Research at the Lank Center for Genitourinary Oncology, and the Marra Lochiatto Investigator at Dana-Farber Cancer Institute, in Boston, Massachusetts.

The recommendation for lenvatinib plus pembrolizumab was based on data from the phase 2 KEYNOTE-B61 trial (NCT04704219), which showed that at a median follow-up of 14.9 months (interquartile range, 11.1-17.4), patients with previously untreated stage IV RCC (n = 148) achieved an objective response rate (ORR) of 49% (95% CI, 41%-57%), including a complete response rate of 6% and a partial response rate of 44%. 2

In a phase 2 trial (NCT03635892), the combination of cabozantinib and nivolumab elicited an ORR of 48% (95% CI, 31.5%-63.9%) in patients with advanced non–clear cell RCC (n = 40). 3

In an interview with OncLive ® , McGregor, who also serves as an assistant professor of medicine at Harvard Medical School, discussed the latest updates to the NCCN Guidelines in kidney cancer, breaking down changes in the non–clear cell space and beyond.

OncLive : What is the importance of the NCCN Guidelines in treatment decision-making for patients with RCC?

McGregor : The NCCN Guidelines remain a critical part of thinking about the management of any cancer. When we look at the NCCN Guidelines, they give an idea of how a large group of experts who meet feel is the best way to approach things; that has implications for how oncologists across the United States think about cancer care.

It also has implications for payers, as well. If [a treatment] is [listed] on the NCCN Guidelines, it certainly will allow for easier coverage when thinking about payer support.

What were some of the most significant changes in the 2024 NCCN Guidelines update in the treatment of kidney cancer?

The largest update with the [updated] NCCN Guidelines was the changes to the approach of the frontline treatment of metastatic [clear cell] RCC. For years now, we’ve had a separation of favorable-, intermediate-, and poor-risk [disease]. When we look at intermediate and poor risk, we had ipilimumab [Yervoy] plus nivolumab as an option, as well as different TKI/immuno-oncology [IO] combinations, [such as] lenvatinib plus pembrolizumab, pembrolizumab plus axitinib [Inlyta], or nivolumab plus cabozantinib, with cabozantinib [monotherapy] as an option as well.

We then look at favorable risk, the 3 IO/TKI [combination] were the standard: nivolumab plus cabozantinib, lenvatinib plus pembrolizumab, or pembrolizumab plus axitinib.

A lot of that was based on the way that the phase 3 CheckMate 214 trial [(NCT02231749) of nivolumab plus ipilimumab] was designed; the primary end point was looking at outcomes in those with poor-risk disease. However, on the initial readouts, the objective response rate and the progression-free survival certainly favored sunitinib [Sutent] monotherapy over nivolumab plus ipilimumab in those with favorable-risk disease with extended follow-up.

Now, we’re seeing a numerically higher overall survival [OS] benefit with a tail to the curve in those patients with favorable-risk disease. With a now 8-year follow-up, the NCCN Guidelines recognized that nivolumab plus ipilimumab plays a role independent of the International mRCC Database Consortium risk category. [Nivolumab plus ipilimumab] is now an option for the frontline treatment of favorable-risk disease.

What was updated in the guidelines for patients with non–clear cell RCC?

Another big change in the NCCN Guidelines is how to approach those patients with divergent histologies, or non–clear cell RCC. The guidelines haven't taken the approach of looking at histology by histology, but we did have some impressive data in the past couple of years [in the advanced non–clear cell space]. We looked at both lenvatinib plus pembrolizumab and nivolumab plus cabozantinib, where we saw activity with IO/TKI doublets in these divergent histologies.

The KEYNOTE-B61 trial showed an ORR of 49% [with lenvatinib plus pembrolizumab], and that included patients with chromophobe, papillary, and translocation [histologies].

In [another] phase 2 trial, nivolumab plus cabozantinib showed an ORR of 48% in those with papillary, translocation, or unclassified [histologies].

Now, the NCCN Guidelines reflect [these data], with lenvatinib plus pembrolizumab and nivolumab plus cabozantinib both listed as potential first-line options, along with cabozantinib [monotherapy].

What is the significance of pembrolizumab being updated to a category 1 recommendation as adjuvant therapy for patients with clear cell histology in the stage II and III pathways?

For years, we've been trying to improve outcomes after surgery for patients with localized RCC. We had several trials with TKIs; [the phase 3 S-TRAC trial (NCT00375674)] showed a disease-free survival [DFS] benefit [with sunitinib vs placebo] but no OS benefit.

Subsequently, we had an explosion of interest in the role of immunotherapy. The phase 3 KEYNOTE-564 trial [NCT03142334] showed a positive improvement in DFS with [adjuvant] pembrolizumab vs placebo in patients with RCC [at intermediate to high risk of disease recurrence]. Pembrolizumab improved DFS with an HR of 0.72 [95% CI, 0.59-0.87]. Updated data presented [at the 2024 Genitourinary Cancers Symposium] showed that [pembrolizumab] not only prevented relapse, but also improved OS. 4 Given that improvement in OS, pembrolizumab is now a category 1 recommendation for adjuvant therapy for those patients who meet the KEYNOTE-564 criteria.

In the adjuvant setting, I feel there's no role for TKI therapy.

What were some of the most significant adjustments made in the surgical and disease management space?

As we think about the role of surgical management in RCC, the NCCN Guidelines reflect that whenever treating localized disease, if a partial nephrectomy is feasible, that's always a preferred approach to optimize kidney function. If the patient has a second primary [tumor, we want to] ensure that the patient is able to undergo definitive local therapy.

When we start thinking about the role of surgical therapy in metastatic disease, the NCCN Guidelines reflect the phase 3 CARMENA trial [NCT00930033] that offers cytoreductive nephrectomy in select patients in combination with systemic therapy, specifically for those with poor-risk features.

Surgery continues to play a role in the treatment of metastatic RCC. There are ongoing trials looking at the role of consolidated nephrectomy, where if a patient starts systemic therapy and has a good response, we then remove the primary [tumor]. Therefore, ongoing studies will certainly help frame how we think about the role of surgery in the treatment of metastatic RCC.

Another other aspect I would make clear is that now we have a nice emphasis on the role for germline testing in the NCCN Guidelines. Who should get those done? Should any patient who has a family history of RCC [be tested].

It is great that we see that right away in the Guidelines now, reflecting what we knew; we know we need to be thinking about this, not just for a patient but for their family members as well.

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2025. Accessed September 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
Lee C-H, Fitzgerald KN, Voss MH, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. J Clin Oncol . 2023;41(suppl 16):4537. doi:10.1200/JCO.2023.41.16_suppl.4537
Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol . 2024,42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359
Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med . 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695

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A new drug candidate can shrink kidney cysts

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Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease, can lead to kidney enlargement and eventual loss of function. The disease affects more than 12 million people worldwide, and many patients end up needing dialysis or a kidney transplant by the time they reach their 60s.

Researchers at MIT and Yale University School of Medicine have now found that a compound originally developed as a potential cancer treatment holds promise for treating ADPKD. The drug works by exploiting kidney cyst cells’ vulnerability to oxidative stress — a state of imbalance between damaging free radicals and beneficial antioxidants.

In a study employing two mouse models of the disease, the researchers found that the drug dramatically shrank kidney cysts without harming healthy kidney cells.

“We really believe this has potential to impact the field and provide a different treatment paradigm for this important disease,” says Bogdan Fedeles, a research scientist and program manager in MIT’s Center for Environmental Health Sciences and the lead author of the study, which appears this week in the Proceedings of the National Academy of Sciences .

John Essigmann, the William R. and Betsy P. Leitch Professor of Biological Engineering and Chemistry at MIT; Sorin Fedeles, executive director of the Polycystic Kidney Disease Outcomes Consortium and assistant professor (adjunct) at Yale University School of Medicine; and Stefan Somlo, the C.N.H. Long Professor of Medicine and Genetics and chief of nephrology at Yale University School of Medicine, are the senior authors of the paper .

Cells under stress

ADPKD typically progresses slowly. Often diagnosed when patients are in their 30s, it usually doesn’t cause serious impairment of kidney function until patients reach their 60s. The only drug that is FDA-approved to treat the disease, tolvaptan, slows growth of the cysts but has side effects that include frequent urination and possible liver damage.

Essigmann’s lab did not originally set out to study PKD; the new study grew out of work on potential new drugs for cancer. Nearly 25 years ago, MIT research scientist Robert Croy, also an author of the new PNAS study, designed compounds that contain a DNA-damaging agent known as an aniline mustard, which can induce cell death in cancer cells.

In the mid 2000s, Fedeles, then a grad student in Essigmann’s lab, along with Essigmann and Croy, discovered that in addition to damaging DNA, these compounds also induce oxidative stress by interfering with mitochondria — the organelles that generate energy for cells.

Tumor cells are already under oxidative stress because of their abnormal metabolism. When they are treated with these compounds, known as 11beta compounds, the additional disruption helps to kill the cells. In a study published in 2011, Fedeles reported that treatment with 11beta compounds significantly suppressed the growth of prostate tumors implanted in mice.

A conversation with his brother, Sorin Fedeles, who studies polycystic kidney disease, led the pair to theorize that these compounds might also be good candidates for treating kidney cysts. At the time, research in ADPKD was beginning to suggest that kidney cyst cells also experience oxidative stress, due to an abnormal metabolism that resembles that of cancer cells.

“We were talking about a mechanism of what would be a good drug for polycystic kidney disease, and we had this intuition that the compounds that I was working with might actually have an impact in ADPKD,” Bogdan Fedeles says.

The 11beta compounds work by disrupting the mitochondria’s ability to generate ATP (the molecules that cells use to store energy), as well as a cofactor known as NADPH, which can act as an antioxidant to help cells neutralize damaging free radicals. Tumor cells and kidney cyst cells tend to produce increased levels of free radicals because of the oxidative stress they’re under. When these cells are treated with 11beta compounds, the extra oxidative stress, including the further depletion of NADPH, pushes the cells over the edge.

“A little bit of oxidative stress is OK, but the cystic cells have a low threshold for tolerating it. Whereas normal cells survive treatment, the cystic cells will die because they exceed the threshold,” Essigmann says.

Shrinking cysts

Using two different mouse models of ADPKD, the researchers showed that 11beta-dichloro could significantly reduce the size of kidney cysts and improve kidney function.

The researchers also synthesized a “defanged” version of the compound called 11beta-dipropyl, which does not include any direct DNA-damaging ability and could potentially be safer for use in humans. They tested this compound in the early-onset model of PKD and found that it was as effective as 11beta-dichloro.

In all of the experiments, healthy kidney cells did not appear to be affected by the treatment. That’s because healthy cells are able to withstand a small increase in oxidative stress, unlike the diseased cells, which are highly susceptible to any new disturbances, the researchers say. In addition to restoring kidney function, the treatment also ameliorated other clinical features of ADPKD; biomarkers for tissue inflammation and fibrosis were decreased in the treated mice compared to the control animals.

The results also suggest that in patients, treatment with 11beta compounds once every few months, or even once a year, could significantly delay disease progression, and thus avoid the need for continuous, burdensome antiproliferative therapies such as tolvaptan.

“Based on what we know about the cyst growth paradigm, you could in theory treat patients in a pulsatile manner — once a year, or perhaps even less often — and have a meaningful impact on total kidney volume and kidney function,” Sorin Fedeles says.

The researchers now hope to run further tests on 11beta-dipropyl, as well as develop ways to produce it on a larger scale. They also plan to explore related compounds that could be good drug candidates for PKD.

Other MIT authors who contributed to this work include Research Scientist Nina Gubina, former postdoc Sakunchai Khumsubdee, former postdoc Denise Andrade, and former undergraduates Sally S. Liu ’20 and co-op student Jake Campolo. The research was funded by the PKD Foundation, the U.S. Department of Defense, the National Institutes of Health, and the National Institute of Environmental Health Sciences through the Center for Environmental Health Sciences at MIT.

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Distribution of methods (A) and equations (B) to estimate kidney function. C, Overall distribution of the kidney function estimation approach according to the enrollment start year. Trials using serum creatinine (sCr) or creatinine clearance (CrCl) level specified that patients could be eligible by meeting either criteria. Vertical bars indicate 1 SE. CG indicates Cockcroft-Gault; eGFR, estimated glomerular filtration rate; and MDRD, Modification of Diet in Renal Disease.

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Karol AB , Paredes R , Fujiwara Y, et al. Heterogeneity in Methods of Estimating Kidney Function for Cancer Clinical Trial Eligibility. JAMA Netw Open. 2024;7(9):e2433387. doi:10.1001/jamanetworkopen.2024.33387

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Heterogeneity in Methods of Estimating Kidney Function for Cancer Clinical Trial Eligibility

1 Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, New York
2 Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, New York
3 Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
4 Icahn School of Medicine at Mount Sinai, New York, New York
5 Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
6 Department of Population Health and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
7 Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York

Kidney function is frequently impaired in patients with cancer due to preexisting chronic kidney disease, cancer-associated factors, and prior anticancer treatments. Given these multifactorial insults, accurate assessment of kidney function is critical to determining patient eligibility for clinical trial enrollment. Measurement of the glomerular filtration rate (GFR) using clearance of exogenous markers provides the most accurate measure of kidney function but is not practical clinically. Although serum creatinine (sCr) level alone has been used to estimate kidney function, it can be influenced by non-GFR physiologic determinants, such as sarcopenia, and nephrology and oncology organization guidelines recommend against using sCr level alone. 1 Several equations incorporating clinical and demographic variables have been developed to improve the estimation of kidney function. 2 Recently, there have been calls for harmonization of most aspects of cancer clinical trial eligibility to foster feasibility, inclusivity, comparability, and generalizability. 3 We sought to understand the landscape of approaches used to estimate kidney function for contemporary cancer clinical trial eligibility.

In this cross-sectional study, ethics approval and consent to participate were not required because the institutional review board of the Icahn School of Medicine did not qualify this study as human research. We systematically searched the ClinicalTrials.gov database to review trial demographics and kidney eligibility criteria for phase 3 clinical trials. Trials were included if completed between October 28, 2013, and October 28, 2023, and if anticancer drugs for adults were evaluated. Trial demographics and methods of kidney function estimates used for trial eligibility were recorded (eMethods in Supplement 1 ). Descriptive statistical analysis was performed using R, version 4.3.2. This study followed the STROBE reporting guideline.

A total of 436 trials met criteria for review, and 231 trials, enrolling 111 424 patients, met the criteria for inclusion. Characteristics of the included trials are shown in the Table ; 139 of 197 (70.6%), 35 of 231 (15.1%), and 200 of 231 (86.5%) trials used the Cockcroft-Gault (CG) formula, sCr level alone, or either CG or sCr level to define kidney function eligibility, respectively ( Figure , A and B). Trends in methods used to estimate kidney function for trial eligibility over time are shown in the Figure , C.

Among 231 phase 3 cancer clinical trials in our analysis, we observed substantial heterogeneity in the methods used to estimate kidney function for clinical trial eligibility. Although professional societies recommend against its use, and despite an improved trend in recent years, 11 of 32 (34.4%) of cancer clinical trials since 2018 still use sCr level alone to define kidney function eligibility. 1 , 3 , 4 The CG formula was the most frequently used equation to estimate kidney function. The CG formula was developed in 1973 using data from 249 men and is known to underestimate kidney function in patients with cancer, and nephrology societies recommend modern approaches to estimate the GFR. 1 Contemporary measures, such as the Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease equations, were used in a few trials. A limitation of our study, however, is that we included only phase 3 trials, which often require less precise kidney function measurements than earlier phase trials.

Despite calls for harmonized clinical trial eligibility across multiple domains, no uniform guidelines currently exist regarding estimation of kidney function. Although various anticancer agents necessitate distinct kidney function thresholds based on their metabolism and toxicity profiles, standardization of methods to estimate kidney function for trial eligibility would foster a comprehensive understanding of the effect of kidney function on adverse events and cancer-related outcomes across clinical trials. Despite momentum to preferentially use the race-free CKD-EPI 2021 formula to estimate GFR, a preferred calculation to estimate kidney function is not well defined. 1 Certain anticancer drugs can also impair tubular secretion of sCr, making accurate estimation of the GFR more challenging. 5 Although cystatin C is another readily available biomarker that may improve GFR estimation, there is concern that certain cancers may affect cystatin C levels endogenouslly. 6 Together, our findings call for a collaborative effort among key stakeholders to establish a standardized approach to estimate kidney function to define cancer clinical trial eligibility.

Accepted for Publication: July 18, 2024.

Published: September 16, 2024. doi:10.1001/jamanetworkopen.2024.33387

Corresponding Author: Alexander B. Karol, MD, Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, 1 Gustave L. Levy Pl, New York, NY 10029 ( [email protected] ).

Author Contributions: Dr Karol had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Karol, Fujiwara, Abramson, Galsky.

Acquisition, analysis, or interpretation of data: Karol, Paredes, Fujiwara, Argulian, Joshi, Galsky.

Drafting of the manuscript: Karol, Joshi, Galsky.

Critical review of the manuscript for important intellectual content: Karol, Paredes, Fujiwara, Argulian, Abramson, Galsky.

Statistical analysis: Karol, Paredes, Fujiwara, Joshi.

Administrative, technical, or material support: Karol, Argulian, Galsky.

Supervision: Abramson, Galsky.

Conflict of Interest Disclosures: Dr Galsky reported receiving personal fees from Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, Seagen, Janssen, Fujiflim, Gilead, Asieris, Veracyte, Daiichi, Astellas, and Aktis outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2 .

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Review Article
Published: 13 September 2024

Polygenic scores and their applications in kidney disease

Atlas Khan ORCID: orcid.org/0000-0002-6651-2725 1 &
Krzysztof Kiryluk ORCID: orcid.org/0000-0002-5047-6715 1

Nature Reviews Nephrology ( 2024 ) Cite this article

Metrics details

Chronic kidney disease
Personalized medicine
Risk factors

Genome-wide association studies (GWAS) have uncovered thousands of risk variants that individually have small effects on the risk of human diseases, including chronic kidney disease, type 2 diabetes, heart diseases and inflammatory disorders, but cumulatively explain a substantial fraction of disease risk, underscoring the complexity and pervasive polygenicity of common disorders. This complexity poses unique challenges to the clinical translation of GWAS findings. Polygenic scores combine small effects of individual GWAS risk variants across the genome to improve personalized risk prediction. Several polygenic scores have now been developed that exhibit sufficiently large effects to be considered clinically actionable. However, their clinical use is limited by their partial transferability across ancestries and a lack of validated models that combine polygenic, monogenic, family history and clinical risk factors. Moreover, prospective studies are still needed to demonstrate the clinical utility and cost-effectiveness of polygenic scores in clinical practice. Here, we discuss evolving methods for developing polygenic scores, best practices for validating and reporting their performance, and the study designs that will empower their clinical implementation. We specifically focus on the polygenic scores relevant to nephrology and other chronic, complex diseases and review their key limitations, necessary refinements and potential clinical applications.

A polygenic score is a numerical measure of inherited susceptibility conveyed by multiple genetic risk variants for a particular trait or disease and is computed by summing the effects of thousands (or millions) of risk alleles across the genome.

Family history and polygenic risk contribute independently to susceptibility for most common complex traits and diseases.

Additive effects of monogenic and polygenic risk have been demonstrated for breast and colorectal cancer, cardiovascular disease and chronic kidney disease.

An integrative genomic risk predictor combines monogenic, polygenic, family history, environmental and clinical risk factors into a single risk prediction framework.

The key limitation of existing polygenic scores is their partial cross-ancestry transferability or diminished predictive performance in various non-European populations currently underrepresented in genome-wide association studies.

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Genome-wide polygenic score to predict chronic kidney disease across ancestries

Impact of hyperuricemia on CKD risk beyond genetic predisposition in a population-based cohort study

Genetics of 35 blood and urine biomarkers in the UK Biobank

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Acknowledgements

The authors’ work is funded by the National Human Genome Research Institute (NHGRI) Electronic Medical Records and Genomics-IV (eMERGE-IV grant 5U01HG008680-07). Additional sources of funding include U01HG013201 (K.K.), R01LM013061 (K.K.), R01DK136765 (K.K.), R01DK105124 (K.K.), RC2DK116690 (K.K.), K25DK128563 (A.K.) and UL1TR001873 (A.K., K.K.).

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Khan, A., Kiryluk, K. Polygenic scores and their applications in kidney disease. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00886-2

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Published : 13 September 2024

DOI : https://doi.org/10.1038/s41581-024-00886-2

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Research Impact: School of Medicine researcher reduces disparities for liver cancer patients

Research Impact is a series that pulls back the curtain of IU Research, showcasing the faculty creating, innovating and advancing knowledge that improves communities and changes lives.

Since she was a little girl, Dr. Lauren Nephew knew she wanted to help people. That desire, coupled with a passion for talking to others and an inquisitive nature, led her to a career as a physician scientist.

Now, Nephew is an assistant professor of medicine in the Division of Gastroenterology and Hepatology and assistant vice chair of health equity at the Indiana University School of Medicine . Her research focuses on understanding the barriers patients face in getting treatment for liver disease and liver cancer, and she is developing tools to remove those barriers.

Question: What is the goal of your research?

Answer: I am a health equity researcher and a liver doctor. I am focused on developing interventions that alleviate health care disparities, particularly for patients with liver cancer and end-stage liver disease, including liver transplant patients.

Beyond just describing the various health disparities between different populations, I am at the point of my research where I am developing interventions to help patients. Indiana University Health is the only liver transplant center in the state, so my main goal is to develop tools that help patients get treatment, and transplant is one of the main treatments for liver cancer.

We have the potential to make a real difference for patients here in Indiana, but lessons we learn here can also be applied across the country.

Q: What tools are your team developing to improve patient outcomes?

A: In talking to patients with liver cancer, we have learned that they feel overwhelmed by the amount of information they receive about their diagnosis and how they receive that information. We have discovered they want to talk to others who have their condition and to feel supported in a way beyond just talking to their physician. We have also learned that they need help navigating the various steps it takes to get from a diagnosis to treatment.

My team has a multi-step approach that includes a social support group for people with liver cancer to engage with each other, education tools that make the information more clear and break it up into modules so it doesn’t come to the patient all at once, and a binder with navigation tools and maps to help patients understand upfront the various steps they’ll need to take to get to a cure. Used together, we hope to help patients with liver cancer achieve better outcomes and reduce disparities.

Q: How is your research helping to address health disparities?

A: In the United States, there are disparities and outcomes in patients based on race, gender, ethnicity, socioeconomic status and geography. There are diseases like liver cancer and end-stage liver disease where certain populations may not do as well as majority populations do. We call that a disparity.

My work is around understanding those disparities – how large it is, who is experiencing this disparity, and, most importantly, what are the determinants? We want to know whether they exist at the neighborhood level, the health system level, the provider level or the patient level. But more than likely, there is a combination of all those reasons for why the disparities are happening. When we can understand the determinants of those disparities, then we can develop solutions to address them.

I have a three-step process of identifying the disparity a group is experiencing, trying to understand the determinants of that disparity and then developing a solution that will lower, and if we’re lucky, completely alleviate that disparity.

Additionally, even though I am a liver doctor, I’m also the associate vice chair for health equity in the Department of Medicine. Our goal is to understand the disparities in care beyond just liver disease, at a population-health level within our health system. I’ve enjoyed looking at some of the problems that exist upstream of liver disease, such as high blood pressure.

Q: What interested you in pursuing research in this field?

A: I became interested in liver disease and liver transplantation when I was in medical school. I had attended a transplant committee meeting where patient information is reviewed and decisions are made about who gets listed for transplant. I looked around at the people making these decisions and the conversations being had, and I realized it was important to have somebody like me in the room.

It is important to have diversity in voice, perspective and lived experience in that kind of setting, and it just wasn’t there. I felt somebody needed to represent the interests of marginalized groups from a place of understanding. That’s how I first became interested in this concept of scarce resource allocation and transplant.

Q: What do you wish people knew about liver disease and liver cancer?

A: I wish people knew that alcohol and viruses are not the only cause of liver disease. Having fat in the liver can cause cirrhosis, permanent scarring of the liver, and people with cirrhosis are at a higher risk of developing liver cancer.

Obesity, diabetes and other risk factors for putting fat in the liver can put someone at an increased risk of liver disease and liver cancer. I don’t think many people realize that.

Q: What do you enjoy most about your work?

A: I really enjoy talking to patients, hearing their solutions and what they think the barriers and needs are. For a long time, people who have developed interventions have come up with solutions on their own. But we are bringing patients into focus groups, telling them about the problems and asking them how they would solve the problems from their perspectives. If we can understand that better, we have a better chance at being effective and improving outcomes.

Kelsey Cook

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Immunotherapy after surgery helps people with high-risk bladder cancer live cancer-free longer

Posted: September 16, 2024

240-760-6600

Drawing of stage II bladder cancer, also known as muscle-invasive bladder cancer. An inset shows cancer in the inner lining of the bladder and in the layer of connective tissue and the muscle layers of the bladder.

Adjuvant pembrolizumab helps people with muscle-invasive bladder cancer remain cancer-free longer than observation alone.

Results from a large clinical trial show that treatment with an immunotherapy drug may nearly double the length of time people with high-risk, muscle-invasive bladder cancer are cancer-free following surgical removal of the bladder. Researchers found that postsurgical treatment with pembrolizumab (Keytruda), which is approved by the Food and Drug Administration (FDA) for treating at least 18 different cancers, was superior compared with observation. The study, led by researchers at the National Institutes of Health (NIH), was published Sept. 15, 2024, in the New England Journal of Medicine .

“This study shows that pembrolizumab can offer patients another treatment option to help keep their disease from coming back,” said lead investigator Andrea B. Apolo, M.D., of the Center for Cancer Research at NIH’s National Cancer Institute (NCI). “Extending the time that these patients are cancer-free makes a big difference in their quality of life.”

A diagnosis of muscle-invasive bladder cancer means the tumor in the bladder has invaded into and through the muscular layer of tissue that encases the bladder. The standard treatment for this form of bladder cancer is to surgically remove the entire bladder. To improve the chances of successful surgery and of eliminating any cancer cells that may have already escaped from the tumor, patients are given cisplatin-based chemotherapy for a period before surgery, known as neoadjuvant therapy, or after surgery, known as adjuvant therapy.

However, many people with muscle-invasive bladder cancer can’t take or refuse neoadjuvant chemotherapy with cisplatin. Others can’t tolerate adjuvant cisplatin-based chemotherapy. Still others, who despite having received neoadjuvant chemotherapy with cisplatin, have persistent muscle-invasive disease but can’t be treated again with adjuvant cisplatin-based chemotherapy. Historically, these groups of patients were instead carefully monitored to watch for signs of relapse.

As an alternative to observation, researchers have been investigating giving patients immunotherapy drugs after surgery to see if it can help them live longer without their cancer coming back.

In 2021, FDA approved nivolumab (Opdivo) as an adjuvant therapy for people with high-risk, muscle-invasive bladder cancer after a clinical trial showed that this immune checkpoint inhibitor—a type of immunotherapy that releases the brakes of T cells so they can recognize and attack tumors—doubled the median length of time patients remained cancer-free compared with a placebo. Adjuvant nivolumab is now the standard of care in this setting.

In the current trial, researchers investigated whether the immune checkpoint inhibitor pembrolizumab would also be effective as an adjuvant treatment. They randomly assigned 702 patients with high-risk, muscle-invasive bladder cancer who had undergone bladder-removal surgery to receive adjuvant therapy with pembrolizumab every three weeks for a year, or to observation for the same period of time. About two-thirds of the patients in the trial had completed neoadjuvant therapy with cisplatin.

After a median follow-up of almost four years, patients in the pembrolizumab group remained cancer-free for a median of 29.6 months, compared with 14.2 months for the observation group. Pembrolizumab was well tolerated, with the most common side effects being fatigue, itching, diarrhea, and an underactive thyroid.

In some cancer types, immune checkpoint inhibitors such as pembrolizumab are more effective against tumors that are PD-L1-positive—that is, the tumor cells produce a large amount of the PD-L1 protein on their surface, than those that don’t, or PD-L1-negative. So Dr. Apolo and her colleagues assessed whether the effect of pembrolizumab varied by PD-L1 status.

Among the 404 patients whose tumors were PD-L1-positive, those treated with pembrolizumab remained cancer-free for a median of 36.9 months, compared with 21 months for those in the observation group. Among the 298 patients whose tumors were PD-L1-negative, those treated with pembrolizumab remained cancer-free for a median of 17.3 months, compared with nine months for the observation group. The researchers concluded that PD-L1 status should not be used to select patients for treatment with pembrolizumab, as both groups benefited from adjuvant pembrolizumab.

In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about 62% of patients in the observation group. The researchers pointed out that many patients in the observation group began taking nivolumab once it was approved or withdrew from the study, which may have skewed the results and made the overall survival data difficult to interpret.

Research teams are already building on the study’s findings by exploring adjuvant treatment using various combinations of drugs with immune checkpoint inhibitors. Researchers are also testing biomarkers to identify patients with high-risk, muscle-invasive bladder cancer who could benefit most from adjuvant treatment of any kind and spare those who may not need it.

The study, known as AMBASSADOR, is sponsored by NCI. The study is being led and conducted by the NCI-funded Alliance for Clinical Trials in Oncology, and it includes participation by NCI’s National Clinical Trials Network as part of Merck’s collaboration with NCI through a Cooperative Research and Development Agreement.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and training extramurally through grants and contracts. NCI’s intramural research program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiological research on the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research at the NIH Clinical Center—the world’s largest research hospital. Learn more about the intramural research done in NCI’s Center for Cancer Research . For more information about cancer, please visit the NCI website at cancer.gov or call NCI’s contact center at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov .

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Foundational Projects

Research in Motion

The Foundational Projects funding program supports high-risk, early-stage projects with the potential to be game-changers in the fields of D2R’s areas of interest.

In the first funding cycle launched in 2024, 47 applications were received of which 17 received awards. View a summary of the review and selection process.

	Project title
Raquel Cuella Martin
Pieter Cullis
Masad Damha
Celia Greenwood
Yann Joly
Nathan Luedtke
Bruce Mazer
Heather Melichar
Nicolas Moitessier
William Muller
Stéphane Richard
Hamed Shateri Najafabadi
Hanadi Sleiman
Nahum Sonenberg
Maryam Tabrizian
David Thomas
Lucienne Tritten

Funded project summaries

Deep mutagenesis approaches to decode t cell receptor-antigen recognition.

To maximize the potential of cancer vaccines, we must enhance the efficacy of T cells, key players in immune responses. Although current vaccines aim to trigger T cells against pathogens or cancer, ensuring they don’t mistakenly attack healthy cells remains a challenge. Moreover, the diversity of T cell receptors and tumor antigens complicates the design of effective and safe cancer vaccines. Our approach combines cutting-edge genome engineering with artificial intelligence to systematically screen for T cell receptors with optimal therapeutic properties. This method aims to crack the T cell receptor recognition code to expedite their optimization for individualized cancer vaccines.'

Principal Investigator: Raquel Cuella Martin (McGill University)

Co-Investigator(s): Heather Melichar (McGill University)

Collaborator(s): Benjamin Haley (Université de Montréal) and Li Xue (Radboud University)

Project duration: Two-year

D2R Axes: Clinical Research, Acceleration, and Implementation (Axis 4) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)

pHREEDOM: A pH-Responsive probe to study Endosomal Escape for RNA Delivery Optimization and Monitoring

Lipid nanoparticles (LNPs) are used to deliver gene therapies like mRNA and siRNA into cells. One current limitation with LNPs is that only a small amount of the genetic material actually reaches the cell interior. This is due to inefficient "endosomal escape," where LNPs get trapped in compartments inside the cell. To better understand and improve this process, we have developed a probe to track the pH inside LNPs as they move through cells. This tool will help us study how well LNPs release their cargo, leading to better designs for gene therapies and more efficient treatments in the future.

Principal Investigator: Pieter Cullis (University of British Columbia)

Co-Investigator(s): Anna Blakney (University of British Columbia)

Collaborator(s): Sabrina Leslie (UBC)

D2R Axes: RNA Therapeutics (Axis 2) Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3)

Engineering a Circular RNA Platform for Cap-Dependent Translation

"Messenger RNA, or mRNA, and its translation into protein lies at the heart of the central dogma of molecular biology. This proposal aims to engineer the first synthetic circular RNA platform to facilitate enhanced protein production and therapeutic applications.

Our long-term objectives include exploring the effects of diverse chemical modifications on circular RNA translation and utilizing novel synthetic chemical methods to produce these molecules tailored for human therapeutics. "

Principal Investigator: Masad Damha (McGill University)

Co-Investigator(s): Sidong Huang (McGill University)

D2R Axes: RNA Therapeutics (Axis 2)

Modelling individual differences in patterns of epigenetic regulation

Advances in technologies combined with decreases in sequencing costs make it feasible to obtain multidimensional measures of epigenetic regulation. Since different aspects of regulation are captured from the range of epigenetic datatypes, in this grant we want to develop statistical methods that optimally combine this prolific, rich information to find key epigenetic patterns and how these patterns change with disease. We will develop these new methods using data generated from individuals before and after infection with influenza.

Principal Investigator: Celia Greenwood (Jewish General Hospital)

Co-Investigator(s): Josée Dupuis (McGill University) and Qihuang Zhang (McGill University)

D2R Axes: Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5) Population Studies and Genomic Medicine (Axis 1)

A first inclusive study on the ELSI aspects of RNA technologies and therapeutics

Our project will be the first to identify ethical, legal, and social issues raised by research and medical practice involving RNA technologies. We will use a “Delphi study” method, in which experts share their views, respond to each other’s perspectives, and revise their own opinions until the group reaches consensus about the most important issues raised by RNA technology. The Delphi study will include scientists, clinicians, policymakers, bioethicists, legal scholars, and social scientists. We will also conduct a series of interviews to gather the perspectives of people representing vulnerable and marginalized groups who may be affected by these technologies.

Principal Investigator: Yann Joly (McGill University)

Collaborator(s): Thomas Duchaine (McGill University), Silvia Vidal (McGill University) and Charles Dupras (Université de Montréal)

D2R Axes: Ethical, Socioeconomic, and Cultural Dimensions in Genomic Research (Axis 6) RNA Therapeutics (Axis 2)

McGill Brand mRNA Production

This project includes mRNA production technologies and student training aimed at establishing a Quebec-based production platform. Our goal is to provide researchers from diverse communities across Canada the ability to generate novel mRNA compositions and associated intellectual property for vaccines and protein replacement therapies. Two new discovery and production platforms will be evaluated for generating natural and chemically modified mRNAs. The production will combine chemical synthesis of RNA oligonucleotides and enzymatic reactions to generate mRNAs with highly diverse chemical structures aimed at enhancing mRNA potency and stability.

Principal Investigator: Nathan Luedtke (McGill University)

Co-Investigator(s): Masad Damha (McGill University) and Maureen McKeague (McGill University)

B-cell derived extracellular vehicles with enriched miRNA contents that mitigate Th2 inflammation

The cost of care for individuals with severe asthma is alarmingly high, accounting for approximately 50% of the cost of asthma therapy in Canada. Current therapies like steroids have high toxicity, or only target individual inflammatory pathways. Biological therapies that potentially act on multiple pathways, with low toxicity, would be advantageous for severe asthma. Using our laboratory-produced B-Cell-derived extracellular vesicles (B2-EV), we simultaneously target multiple genes via a combination of miRNA. B2-EV will be tested using well-established preclinical mouse asthma models and spatial transcriptomics and proteomics to allow us to perform robust proof-of-concept experiments addressing the molecular basis for B2-EVs as a potential therapy for severe asthma.

Principal Investigator: Bruce Mazer (Research Institute of the McGill University Health Centre)

Co-Investigator(s): Janusz Rak (Research Institute of the McGill University Health Centre)

Collaborator(s): Yasser Riaz Al-Hosseini (McGill University)

Enabling low-cost, massive-scale sequencing of antigen receptors for personalized immunotherapy

T cells identify and eliminate infected and cancer cells. They recognize diseased cells via their antigen receptor. Each T cell has a unique antigen receptor. There are hundreds of millions of T cells that patrol for diseased cells. Identifying antigen receptors is expensive and low throughput. We propose new technology that will allow for marked cost reductions and a massive increase in the number of antigen receptors that can be sequenced at once. This will have a broad impact on fundamental research and clinical applications that include testing the efficacy of emerging vaccines and expediting development of adoptive cell therapies.

Principal Investigator: Heather Melichar (McGill University)

Co-Investigator(s): Judith Mandl (McGill University) and Claudia Kleinman (Lady Davis Institute/McGill University)

Collaborator(s): Benjamin Haley (Université de Montréal)

D2R Axes: Clinical Research, Acceleration, and Implementation (Axis 4) Population Studies and Genomic Medicine (Axis 1)

RNA-targeting therapeutics to address antimicrobial resistance

RNA elements known as riboswitches control genes in bacteria and have not been found in humans. There are ongoing efforts to develop molecules that bind to riboswitches and alter gene expression, thereby impacting growth of pathogenic bacteria. Such molecules could become the next generation of antibiotics. However, there are many unsolved challenges in targeting riboswitches including host toxicity or antimicrobial resistance by accumulating mutations in the riboswitch. To overcome these challenges, we assembled a team to design riboswitch-targeting antibiotics. Using computer simulations and high-throughput assays, we will identify molecules that bind to and alter riboswitch shape, minimizing bacterial resistance

Principal Investigator: Nicolas Moitessier (McGill University)

Co-Investigator(s): Maureen McKeague (McGill University) and Anthony Mittermaier (McGill University)

D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5)

Targeting an alternative oncogenic Human Epidermal Growth Factor Receptor 2 splice isoform

Breast cancer is one of the most prevalent cancers afflicting human female populations. Despite the development of new therapies, morbidity and mortality from breast cancer remain critical issues due to acquisition of resistance to targeted therapies. Preliminary work from our group has shown that a variant of the HER2 oncogene known as HER2Δ16 which is generated by alternative splicing resulting in skipping of Exon 16 is a potent oncogenic variant of HER2 capable of inducing multifocal metastatic in mammary tumors in Genetic Engineered Mouse Models (GEMMs). This form of HER2 lacks a small portion of its protein sequence in juxta-transmembrane region that facilitates dimerization of receptor leading to constitutive activation of HER2 tyrosine kinase. We have further shown that HER2Δ16-derived tumors are highly resistant to the Trastuzumab-derived T-DM1 conjugated antibody and small molecule kinase inhibitors implicating this isoform as a potential determinant of resistance to HER2 targeted therapies. Finally, we recently showed that expression HER2Δ16 can be detected in over 40% of HER2 positive breast cancer that is further correlated with poor clinical outcome. Despite the pressing need for reagents that specifically target this oncogenic HER2 splice isoform, to date no therapeutic agent is available that specifically targets this isoform. In this D2R proposal, we plan to identify and evaluate whether shRNAs targeting the splice junction could be used to target this oncogenic variant. In a related approach we will also identify key transacting factors regulating exon 16 skipping and assessing whether targeting these factors is a viable approach in preventing formation of the HER2Δ16 oncogenic variant. Results from these studies could alter current clinical practice with HER2-targeted therapies.

Principal Investigator: William Muller (McGill University)

Collaborator(s): Sidong Huang (McGill University)

Defining the role of arginine methyltransferases in the regulation of intronic circular non-coding RNAs in diseases

Circular intronic RNAs (ciRNAs) are single-stranded, covalently closed RNAs derived from intron lariats circularized by 2′–5′ junctions. Although their functions are still largely unexplored, aberrant expression of certain ciRNAs has been recently found in different human diseases. We discovered that the protein arginine methyltransferase 5 (PRMT5), a promising cancer drug target, plays an important role for the regulation of ciRNA expression. We will explore potential applications of PRMT5-regulated ciRNAs as non-invasive diagnostic and prognostic biomarkers for cancers and therapeutic reagents in human diseases such as Amyotropic Lateral Sclerosis (ALS) and cancer.

Principal Investigator: Stéphane Richard (Jewish General Hospital)

D2R Axes: Population Studies and Genomic Medicine (Axis 1) RNA Therapeutics (Axis 2)

Single-cell and spatial profiling of RNA splicing to understand tumour heterogeneity

Abnormalities in how genes are processed, particularly through a process called splicing, play a key role in many diseases, including cancer. This project aims to develop new tools to study gene splicing at the single-cell level, which will help us better understand how it varies between individual cells in a tumor. By combining advanced sequencing technologies with novel computational algorithms, we will create a detailed map of splicing in kidney cancer cells. This approach will provide new insights into how splicing influences cell behavior in cancer and could lead to better understanding and treatments for this disease.

Principal Investigator: Hamed Shateri Najafabadi (McGill University)

Co-Investigator(s): Yasser Riazalhosseini (McGill University) and Ioannis Ragoussis (McGill University)

Collaborator(s): Hani Goodarzi (University of California San Francisco)

D2R Axes: Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5) RNA Therapeutics (Axis 2)

DNA Nanoparticles for Targeted Therapy Against Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive blood cancer affecting around 1300 Canadians annually, with current therapies only curing 30% of patients. We have developed safe, controllable delivery vehicles for nucleic acid therapeutics, showing enhanced activity in many animal cancer models. We propose to develop nucleic acid therapies to target AML stem cells, which contribute to drug resistance and relapse. These structures will carry cancer therapeutics specifically to AML cells, sparing healthy cells and reducing toxic side effects, improving treatment efficacy and minimizing relapse.

Principal Investigator: Hanadi Sleiman (McGill University)

Co-Investigator(s): Francois Mercier (McGill University, Lady Davis Institute)

D2R Axes: Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3) RNA Therapeutics (Axis 2)

Live Imaging of mRNA 5′ cap Interaction with translation initiation factors

In eukaryotic cells, the process of mRNA translation (making proteins from mRNA) begins when a specific protein complex called eIF4F interacts with the "cap" at the beginning of mRNA. Our research aims to examine how individual proteins involved in translation interact with the mRNA cap in real-time inside cells. Additionally, we will study how viral proteins, and other factors interfere with this process. The goal is to use this information to improve the design and effectiveness of future mRNA vaccines.

Principal Investigator: Nahum Sonenberg (McGill University)

Co-Investigator(s): Maria Vera Ugalde (McGill University) and Paul Wiseman (McGill University)

Collaborator(s): Jacek Jemielity (University of Warsaw)

Iron/siRNa-Based Dynamic Delivery System Boosting Ferroptototic Cell Death in Metastatic Melanoma

Melanoma has traditionally been resistant to chemotherapy. In addition, acral and uveal melanoma subtypes are typically insensitive to immune checkpoint inhibitor therapeutics, where the 5-year survival rates are <30%. While, the 6.5-year survival rates (57-46%) have improved for patients with advanced cutaneous disease, many still do not respond, thereby necessitating the discovery and development of better therapeutics to significantly improve patient survival. Our goal for this proposal is to develop highly potent RNA-based therapeutics to introduce ferroptosis as a treatment modality for patients with unresectable melanoma for whom surgery is not an option or for whom checkpoint inhibitors are contraindications.

Principal Investigator: Maryam Tabrizian (McGill University)

Co-Investigator(s): Danuta Radzioch (McGill University), Sonia V. del Rincón (McGill University) and David Juncker (McGill University)

Collaborator(s): André Charette (Université de Montréal)

Dominant Negative RNA: A novel approach to CFTR gene therapy

CF is a protein trafficking disease where the mutant, but otherwise functional gene is recognized by the cell’s quality control system. We have identified genes that correct the trafficking defect of mutant CFTR. We have shown that the inactive versions of these genes are the active agents in correcting mutant CFTR The uniqueness of this approach is that that the inactive versions of the two genes correct the trafficking of mutant CFTR trafficking. We have shown that the shRNA in lentivirus versions of these genes can efficiently correct CFTR trafficking. we are currently refining their potential for CF gene therapy in cells from cystic fibrosis patients.

Principal Investigator: David Thomas (McGill University)

Co-Investigator(s): John Hanrahan (McGill University)

Collaborator(s): Michelle Scott (Université de Sherbrooke)

Using native gut bacteria to release RNA therapeutics against intestinal nematode infections

Parasitic helminths inflict neglected tropical diseases upon humans and cause substantial losses in agriculture. Despite efforts, control interventions still face major challenges, exacerbated by the rapid emergence of drug resistance, particularly among livestock parasites. Therefore, it is imperative to explore alternative treatments for these infections. Leveraging emerging evidence of inter-kingdom extracellular vesicle exchange and our recent advancements in engineering native transgenic bacteria capable of engrafting in their original mammalian hosts, I aim to investigate the potential of bacteria-produced noncoding RNAs as anthelmintic agents. The objectives of this research endeavor include: i) Developing native E. coli tools to specifically target helminths both in vitro and in vivo at the site of infection, and ii) Identifying foreign noncoding RNA, originating from the host and the surrounding commensal microbiota, that interacts with worm messenger RNA, potentially regulating parasite gene expression. For modeling purposes in vitro, we will rely on Caenorhabditis elegans, and for in vitro and in vivo experiments, we will employ the mouse intestinal nematode parasite Heligmosomoides polygyrus bakeri. The innovation of this study lies in investigating the efficacy of miRNA targeting against helminth infections and utilizing commensal bacteria as carriers for anthelmintic molecules. This project harbors significant translational potential, aiming to address critical questions hindering progress in RNA therapeutics for parasitic diseases. Upon completion, this research will shed light on: i) the potential utility of antagonizing helminth miRNAs and other targets for treating or preventing helminth infections, thereby elucidating the role of miRNAs in the infection's development and maintenance, and ii) the viability of utilizing live bacteria therapeutics against helminth infections. This data will enrich our qualitative and quantitative understanding of EV and miRNA trafficking in the gut, serving as a cornerstone for future targeted investigations (e.g., on the molecules involved in spatiotemporal EV and RNA trafficking within worm tissue) and facilitating the acquisition of larger funding opportunities, such as CIHR and NIH grants."

Principal Investigator: Lucienne Tritten (McGill University)

Collaborator(s): Amir Zarrinpar (University of California San Diego) and Oliver Rossbach (Justus-Liebig University of Giessen)

D2R Axes: RNA Therapeutics (Axis 2) Data Science, Bioinformatics, and Computing in Personalized Medicine (Axis 5) , Bioprocessing, Biomanufacturing, and Nanotechnology (Axis 3)

Department and University Information

D2r | dna to rna.

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Advances in Kidney Cancer Research
Today, about 75% of people with kidney cancer will be alive 5 years after diagnosis. This page highlights some of the latest research in kidney cancer, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.
Advances in treating kidney cancer
By DeeDee Stiepan. Kidney cancer is one the most common cancers in the U.S., with 81,610 new cases estimated in 2024. Mayo Clinic sees a high volume of kidney cancer cases and is among the most experienced institutions in treating kidney tumors.
What's New in Kidney Cancer Research
With 87 new interventional studies since January 2023, the research landscape is vibrant and full of potential. Here, we translate complex research into practical insights, offering a beacon of hope and knowledge for the kidney cancer community. Join us as we delve into the trials and breakthroughs that are defining the future of kidney care.
What Doctors Are Excited About in Kidney Cancer Research
And with numerous other therapies being developed by pharmaceutical companies at the same time as others are making their way through clinical trials, the future for kidney cancer patients is ...
What's New in Kidney Cancer Research?
In the last couple of decades, newer types of drug treatments have emerged as the most effective treatment options for most advanced kidney cancers. Targeted drugs attack specific parts of cancer cells (or nearby cells that help them grow, such as the cells that make new tumor blood vessels). Immunotherapy drugs help the body's own immune ...
FDA Approves New Treatment for Advanced Kidney Cancer
The Food and Drug Administration last week approved Welireg (belzutifan) for patients with advanced kidney cancer who previously used other types of treatment. The December 14 decision marks the first approval of a new class of therapy for advanced renal cell carcinoma (RCC), the most common type of kidney cancer, in nearly a decade.. Welirig is a hypoxia-inducible factor 2 alpha (HIF-2α ...
Kidney Cancer Research Articles
Find research articles on kidney cancer, which may include news stories, clinical trials, blog posts, and descriptions of active studies. ... (PRCC), a rare type of kidney cancer. A clinical trial showed the drug was more effective than the current standard treatment. Liquid Biopsy Detects Brain Cancer and Early-Stage Kidney Cancer.
FDA approves kidney cancer therapy after Dana-Farber-led research shows
The FDA approval was based on results of the phase 3 LITESPARK-005 trial, a study led by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute. Findings from LITESPARK-005 were presented at the European Society of Medical Oncology annual meeting in October 2023.
Adjuvant Keytruda Improves Kidney Cancer Survival
The immunotherapy drug pembrolizumab (Keytruda) has rapidly become one of the most widely used cancer treatments. Based on updated results from a large clinical trial, the drug is now part of an important milestone in the treatment of kidney cancer—specifically, clear-cell renal cell carcinoma, the most common form of the disease.. All participants in the trial had earlier-stage kidney ...
Renal cancer
Renal cancer articles from across Nature Portfolio. Renal cancer refers to all malignancies that occur within the kidney. Subtypes include renal cell carcinoma and Wilms tumours. Renal cell carcinoma.
Major developments in kidney cancer in 2021
December 22, 2021. Radha Chitale. Research. 2021 was a bumper year for kidney cancer developments, including several new treatment approvals by the FDA and a much better understanding of how kidney cancer is impacted by COVID-19 infections and vaccines. "All are very important topics that are affecting patients as we speak," said Nancy ...
The Latest Kidney Cancer Treatment Advances: What to Know
Kidney cancers are among the top 10 most common cancers in both men and women: about 79,000 new cases will be diagnosed in 2022, according to the American Cancer Society. When the cancer is first ...
Advances in kidney cancer research and care
The American Cancer Society estimates that more than 81,500 people will be diagnosed with kidney cancer in the United States this year, and the disease will cause 14,300 deaths. While the ...
Risk Prediction Models for Kidney Cancer: A Systematic Review
1. Introduction. Kidney cancer is the 15th most common cancer worldwide, with a significantly higher incidence in developed countries .And the incidence is projected to rise in coming years , .In Europe, kidney cancer was responsible for >50 000 deaths in 2018 , .Early detection and screening have been identified as priorities for kidney cancer research , .
Combination treatment doubles survival for patients with advanced
A small clinical trial suggests that a duo of drugs can extend survival for people battling advanced kidney cancer. Researchers at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y ...
Scientists develop novel antibody treatment for kidney cancer
Scientists develop novel antibody treatment for kidney cancer. ScienceDaily . Retrieved September 12, 2024 from www.sciencedaily.com / releases / 2024 / 06 / 240604132003.htm
Renal cell carcinoma
Latest Research and Reviews ... Research Highlights 26 Jul ... macrophages showing immunogenic interactions is predictive of the response to immunotherapy in patients with advanced kidney cancer. ...
Renal cell carcinoma treatment: What's new and what's next
Request an appointment at MD Anderson online or by calling 1-877-632-6789. Read More by Molly Adams. Pavlos Msaouel, M.D., Ph.D., shares current renal cell carcinoma treatment approaches and how a clinical trial he is co-leading with Chad Tang, M.D., is exploring adding radiation therapy as an option for metastatic disease.
Combo Treatment Doubles Survival for Patients With Advanced Kidney Cancer
TUESDAY, Sept. 17, 2024 (HealthDay News) -- A small clinical trial suggests that a duo of drugs can extend survival for people battling advanced kidney cancer.
Management of advanced kidney cancer: Kidney Cancer Research Network of
The current consensus statement is based on the deliberations and conclusions of key Canadian opinion leaders in the management of advanced renal cell cancer who convened during the 11th Canadian Kidney Cancer Forum, held virtually on October 16, 2020. ... The following is a consensus report from the Kidney Cancer Research Network of Canada ...
Updated NCCN Kidney Cancer Guidelines Bring New Recommendations for
The changes in the 2024 update to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the treatment of patients with kidney cancer include new ...
A new drug candidate can shrink kidney cysts
At the time, research in ADPKD was beginning to suggest that kidney cyst cells also experience oxidative stress, due to an abnormal metabolism that resembles that of cancer cells. "We were talking about a mechanism of what would be a good drug for polycystic kidney disease, and we had this intuition that the compounds that I was working with ...
Combo Treatment Doubles Survival for Patients With Advanced Kidney Cancer
Some patients with advanced kidney cancers were good candidates for powerful immunotherapy cancer medicines, but George's team noted that pazopanib/bevacizumab might be a safer option for some. The combo drug therapy had "superior safety compared with immunotherapy combinations," the researchers noted in a Roswell news release.
Heterogeneity in Methods of Estimating Kidney Function for Cancer
The CG formula was developed in 1973 using data from 249 men and is known to underestimate kidney function in patients with cancer, and nephrology societies recommend modern approaches to estimate the GFR. 1 Contemporary measures, such as the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease ...
Kidney Cancer Resources
Kidney cancer starts in the kidneys and can lead to tumors. Symptoms may include blood in urine and back pain. Risk factors include smoking, obesity, and high blood pressure. ... The Latest in Kidney Cancer Research. Search for kidney cancer related articles from one of our journals or professional publications.
Polygenic scores and their applications in kidney disease
Genome-wide association studies (GWAS) have uncovered thousands of risk variants that individually have small effects on the risk of human diseases, including chronic kidney disease, type 2 ...
AstraZeneca and MSD hail progress in hard-to-treat cancers
The results are the latest successes for Keytruda and Imfinzi, two drugs known as "checkpoint inhibitors", which prevent cancer cells from disabling immune cells' response to tumours ...
Research Impact: School of Medicine researcher reduces disparities for
Research Impact is a series that pulls back the curtain of IU Research, showcasing the faculty creating, innovating and advancing knowledge that improves communities and changes lives. Since she was a little girl, Dr. Lauren Nephew knew she wanted to help people. That desire, coupled with a passion for talking to others and an inquisitive ...
Pembrolizumab improves outcomes in high-risk bladder cancer
For more information about cancer, please visit the NCI website at cancer.gov or call NCI's contact center at 1-800-4-CANCER (1-800-422-6237). About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services.
Foundational Projects
The Foundational Projects funding program supports high-risk, early-stage projects with the potential to be game-changers in the fields of D2R's areas of interest. In the first funding cycle launched in 2024, 47 applications were received of which 17 received awards. View a summary of the review and selection process. Principal Investigator Project title Raquel Cuella Martin Deep mutagenesis ...

Advances in treating kidney cancer

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Management of advanced kidney cancer: Kidney Cancer Research Network of Canada (KCRNC) consensus update 2021

Anil Kapoor

Naveen S. Basappa

Georg Bjarnason

Dominick Bossé

Jeffrey Graham

Samantha Gray

Aaron R. Hansen

Daniel Y.C. Heng

Pierre I. Karakiewicz

Christian Kollmannsberger

Aly-Khan A. Lalani

Scott A. North

Denis Soulières

Myuran Thana

Eric Winquist

Lori A. Wood

Sebastien J. Hotte

1. Management of locally advanced kidney cancer