More Options in Renal Cell Carcinoma Treatment Means Greater Hope For Patients

George Benson wasn’t concerned when he began experiencing lower abdominal pain in August 2009. Between a busy career and family life, with vacations planned and a son returning from the military, Benson, then 51, put off seeing a doctor.

“I thought it was a hernia,” says the truck driver from southeastern Michigan.

The pain persisted, then worsened, and Benson eventually saw his primary care doctor, who ordered blood tests and a CT scan. A landscape and abstract artist, Benson was shopping for a canvas when his doctor called with the news: Benson had a suspicious mass about the size of a softball over his left kidney.

“When I sat down with the urologist a week later, he showed me the mass and said he was 95% sure it was cancer,” Benson says. “To me, the mass looked like a fist wrapped around a fortune cookie.”

At the time, Benson didn’t realize his fortune would include becoming part of the changing face of advanced kidney cancer treatment. Within weeks, doctors cut off the tumor’s blood supply and he underwent surgery to remove the 10-pound mass. That was just the beginning of Benson’s decade-long treatment journey, which included participating in two clinical trials.

Over 70,000 Americans each year receive diagnoses of renal cell carcinoma or kidney cancer.

The five-year survival rate for patients with early-stage disease is more than 90% compared with less than 15% for those with advanced kidney cancer. Unfortunately, catching the disease early can be a challenge. Symptoms are vague and easily explained, and in the absence of certain predisposing genetic conditions, such as von Hippel-Lindau (VHL) syndrome and hereditary renal carcinoma, kidney tumors are frequently missed.

“We don’t have a good blood- or urine-based diagnostic test that might help us detect early stage kidney cancer,” says Dr. David McDermott, director of the biologic therapy and cutaneous oncology programs at Beth Israel Deaconess Medical Center in Boston. In fact, kidney cancer at any stage is often uncovered by a CT scan or ultrasound performed for another reason.

Unlike other solid tumors, such as breast, prostate and lung, kidney cancer is primarily driven by abnormally formed blood vessels. “The kidney cells and cancer cells sense a lack of oxygen (cellular hypoxia), even when there’s plenty of oxygen,” explains Dr. Ajjai Shivaram Alva, an associate professor at Michigan Medicine in Ann Arbor. The faulty mechanism causes the body to form new blood vessels that fuel the cancer.

With rare exceptions, kidney tumors do not shrink with chemotherapy or radiation.

Fortunately, Nobel Prize-winning research uncovered pathways that drive the growth and spread of kidney cancer, leading to the development of targeted treatments. Plus, scientists have long known that, like melanoma, kidney cancer is an immune-responsive tumor, opening the door to with the use of novel immunotherapies. Add it all up and doctors have more tools than ever before to combat kidney cancer.

Scientists are still working out which tumors respond to different treatments and why clear cell disease is often more sensitive to therapy. But according to McDermott, there’s reason to hope that immunotherapies known as checkpoint inhibitors, particularly in combination with other novel agents, can improve survival rates for patients with kidney cancer. The key, he says, will be targeting not only the microenvironment that supports the tumor (for instance, blood vessels) but also the tumor cells.

CHOOSING A TREATMENT ON TRIAL

Historically, doctors treated kidney cancer with surgery, which is still a mainstay of treatment, especially for patients with disease in stages 1 to 3. But for one-third of patients, the cancer returns after surgery, possibly because cancerous cells have traveled to nearby lymph nodes or entered the blood supply. “Research is underway to understand whether preemptively attacking leftover cancer cells after surgery can help prevent recurrence,” Alva says.

Those options weren’t even a pipe dream when Benson received a diagnosis of stage 3b disease. After his surgery, he had follow-up CT scans done every three months for two years, then every six months for a few more years. In March 2016, a scan uncovered growth in a nodule on his right lung.

Benson’s best treatment option at the time was interleukin-2, a therapy that boosts the growth and activity of immune cells called lymphocytes. The problem: often intolerable side effects. “Your blood pressure drops so low (that) you can’t stand on your own,” Benson says. The drug also can cause fever, nausea, aches and pains, fast heartbeat and changes in liver function.

Between 2005 and 2010, a new wave of less toxic therapy options emerged, and survivorship after kidney cancer grew dramatically. Because all cells, even cancerous ones, need oxygen, Dr. William Kaelin Jr., a professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute in Boston, set out to understand how the body senses and adapts to changes in oxygen levels.

“For years, scientists have known that mutations in the tumor-suppressor gene VHL led to von Hippel Lindau syndrome, a rare disorder that makes patients more vulnerable to kidney cancer,” says Dr. Toni Choueiri, director of genitourinary oncology at Dana-Farber. In 2019, Kaelin, a collaborator of McDermott and Choueiri, was a winner of the Nobel Prize in medicine for uncovering how cells adjust to changes in oxygen availability and how glitches in that process can lead to cancer. Kaelin, along with Dr. Gregg L. Semenza of Johns Hopkins Medicine in Baltimore and Dr. Peter J. Ratcliffe of the Francis Crick Institute in London, demonstrated that the protein made from a mutated VHL gene causes a cell to erroneously sense hypoxia, leading to expression of a protein called hypoxia-inducible factor-1 (HIF-1)-alpha and activation of genes involved in blood vessel formation, including VEGF.

Cancer cells with a mutated VHL gene use that chain of events to surround themselves with new blood vessels that feed their growth. So, Kaelin thought, what if that blood supply was cut off? This work led to clinical testing of drugs called VEGF receptor inhibitors, including Sutent (sunitinib), Votrient (pazopanib), Cabometyx (cabozantinib), Inlyta (axitinib) and Nexavar (sorafenib), and the creation of more than a dozen new therapy options.

LAUNCHING A TARGETED ATTACK

In the fall of 2006, 51-year-old Shaun Tierney and his wife, Mary, were enjoying their newly empty nest when he felt a tug in his groin muscle while playing golf. Suspecting bursitis of the hip, Tierney’s doctor prescribed high doses of Aleve (naproxen).

The pain worsened over several months, ultimately radiating up Tierney’s right side. In February 2007, his doctor ordered an ultrasound. Tierney, an engineer from western Massachusetts, had stage 4 bilateral kidney cancer. The disease had already spread to his lungs, liver and bones.

“The oncologist told me the cancer was inoperable and resistant to chemotherapy and radiation — and that I should get my affairs in order,” Tierney says. Because he had received a diagnosis of multiple sclerosis at age 31, Tierney wasn’t eligible for immune-based therapies such as interleukin-2. Unwilling to give up, he went to Dana-Farber for a second opinion. “That’s when the tide started to shift from total desperation toward a vision for the future,” he says.

Shortly before Tierney’s cancer diagnosis, the Food and Drug Administration (FDA) had approved the VEGF inhibitor Sutent to treat kidney cancer, and doctors at Dana-Farber were already using the drug as a first-line defense against advanced cases.

After 12 sessions of targeted high-dose radiation therapy, Tierney started on Sutent, and within six months, many of the tumors had shrunk by 50%. “That proved to be a very successful strategy, with response rates in up to 40% of patients,” Choueiri says. “It didn’t cure cancer, but it allowed patients to live longer.”

Tierney took the drug for 13 years with scheduled 10- to 14-day breaks, but it was not an easy regimen. Because Sutent blocks blood vessel formation, it produces a host of side effects. Blood vessels become more rigid and blood pressure levels can skyrocket; patients may also experience nausea, vomiting, severe diarrhea, fatigue and low blood counts, and many have trouble tolerating long-term treatment.

Choueiri, Tierney’s oncologist, made many adjustments to his treatment doses and cycle times to minimize toxicities, but the side effects became increasingly severe. Toward the end of his Sutent odyssey, Tierney’s quality of life was severely affected. The good news is that there are many other options now: During the 13 years since Tierney received his diagnosis, the FDA approved 14 treatments to treat kidney cancer. These mainly include immunotherapies and targeted drugs, plus a couple of mTOR inhibitors designed for use after preferred medications stop working.

FIGHTING CANCER WITH IMMUNE-BASED COMBINATIONS

Dating back 30 years, scientists saw deep responses and even remission with immune-based interleukin-2 therapy among a subset of patients with kidney cancer. That told doctors that kidney cancer, like melanoma, responds to immunotherapy. In 2015, the FDA approved the first checkpoint inhibitor for the treatment of kidney cancer.

This unique class of drugs works by inhibiting proteins that keep the immune system in check, thus unleashing it to fight cancer.

Unlike the cytokines of the 1990s, such as interleukin-2, checkpoint inhibitors create a more targeted immune response. “With that, we’ve seen a tremendous uptick in the degree of clinical benefits patients are deriving from therapy,” says Dr. Sumanta (Monty) Kumar Pal, a medical oncologist at City of Hope, a comprehensive cancer center in Duarte, California. Pal calls this new class of drugs Immunotherapy 2.0.

Based on work done in other tumor types, scientists began combining checkpoint inhibitors that block the activity of the proteins PD-1 and/or PD-L1, including Opdivo (nivolumab), Keytruda (pembrolizumab) and Bavencio (avelumab), with checkpoint inhibitors that block the activity of the protein CTLA-4, such as Yervoy (ipilimumab). In April 2018, the FDA approved a combi- nation of Opdivo and Yervoy after a landmark study proved the immunotherapy regimen superior to Sutent. Not only did patients in the combination group gain a survival benefit, but about 10% of them also experienced a persistent and durable remission.

In early 2019, scientists began combining VEGF-targeted treatment and immunotherapy with jaw-dropping results. Response rates for the combined treatment reach up to 60% compared with 40% using a single agent, Choueiri says. Research suggests these novel therapies may even supersede surgical removal of the tumor in some cases.

“Those two regimens, PD-1 plus CTLA-4 and PD-1 plus a VEGF inhibitor, are new standards of care in the front lines,” McDermott says. “What we lack is head-to-head data, so we can’t determine which approach is superior or which combination should be used in which patient.” Some researchers suspect that creating a triplet therapy — VEGF inhibitor plus PD-1 plus CTLA-4 — could coax the response rate to climb even higher.

The big question is whether patients must remain on treatment indefinitely to continue experiencing benefit. According to McDermott, scientists need to do more studies to determine how safe it is to stop treatment in patients with deep responses. “It may be that if you get beyond 50% shrinkage or 80% shrinkage, you can take a break,” he says. “We don’t know what that cutoff is, but we know that the deeper your response, the more likely you are to be alive at five years.”

NAVIGATING A NEW FRONTIER

With so many treatment options for advanced kidney cancer, oncologists often aren’t sure which road to travel first. “One good way to figure that out is to calculate the patient’s risk score by evaluating certain variables,” Pal says. These include the patient’s white and red blood cell counts, overall function and lymph node involvement. “Using these parameters, we can tell if they fall into a favorable risk category, an intermediate-risk category or a poor-risk category,” he says.

For intermediate and poor-risk patients, doctors tend to side with a PD-1/CTLA-4 immunotherapy combination. For those with favorable risk, most oncologists start with traditional targeted agents, including VEGF inhibitors, or a combination therapy with a PD-1 inhibitor and a VEGF inhibitor. This way, the side effects and risks of the therapy are balanced against the aggressiveness of the tumor to create the most favorable risk/benefit ratio.

Still, oncologists and patients alike need to tread carefully.

“It’s important for people to understand that with immune-based therapies, side effects may not happen right away,” Pal says. “When you overstimulate the immune system, you can get serious side effects like diarrhea or liver function abnormalities, but those may come on weeks after initiating therapy.”

Patients like Tierney, who have an autoimmune condition, even a controlled one, are at greater risk of triggering a catastrophic immune reaction. Because Tierney’s multiple sclerosis has been dormant for 12 years, Choueiri prescribed a combination of the infused PD-1 drug Keytruda every three weeks and a daily oral VEGF inhibitor, Inlyta, in March. The regimen is the same as what would be prescribed for a patient without an autoimmune condition; Benson has been taking it since September 2019.

No matter which regimen they try first or last, many patients are alive because they participated in clinical trials. “Many of my long-term patients started therapies five to seven years before they were FDA approved because they were involved in a clinical trial,” Alva says.

The next round of trials may focus on HIF-1-alpha; the oxygen-sensitive protein can trigger or suppress the production of red blood cells and the formation of new blood vessels.“UnlikeVEGF,PD-1andCTLA-4blockade,HIF inhibitors more directly target one of the drivers of kidney cancers,” McDermott says. “They also have a very favorable toxicity profile, which makes them a potential candidate for combination therapies.” The first trial of a HIF-2a inhibitor (MK-6482), in patients who had prior treatment for renal cell cancer, recently reported responses, and now randomized trials are planned.

As researchers uncover more options for treating advanced kidney cancer, the beneficiaries of their hard work — patients like Tierney and Benson — are welcoming grandchildren, traveling the world and adopting new hobbies, living on time afforded them by the therapies available so far.

Since starting treatment at Dana-Farber in early 2007, Tierney has joined several grassroots, advocacy groups.

He is a patient representative for Dana-Farber/Harvard Cancer Center’s kidney cancer program, raising money for kidney cancer research through the Jimmy Fund. He also supports others with kidney cancer, both in person and through a global online community.

Benson continues working for the chair manufacturer that supported him during and after his diagnosis. He loves spending time with his three children and traveling with his wife, Brenda. In fact, she transitioned from an emergency room nurse to one specializing in oncology while Benson underwent treatment. The pair will celebrate their 35th wedding anniversary in July.

Both patients agree that receiving their diagnoses when they did allow them to benefit from advances in research and treatment that gave them a fighting chance. And now that scientists are on the cusp of uncovering even more treatment options for advanced kidney cancer, “there’s reason to be hopeful,” McDermott says.