A Sign of the Times: The Changing Treatment Landscape for Advanced Kidney Cancer

Whenever 60-year-old Catherine Messinger experienced pain in her side, she would chalk it up to diverticulitis, a condition that had plagued her for many years. But in April 2013, her intense pain signaled something else. Messinger, whose doctor initially suspected a kidney stone, had a tumor on her kidney and was diagnosed with stage 4 renal cell carcinoma (RCC), or kidney cancer.

After Messinger underwent several months of scans to monitor her progress, a new tumor was found in her spine and, in January 2014, despite initial treatment, her doctors found that the tumor had spread to her abdomen. Messinger needed innovative treatment, and, luckily, she qualified for the one spot her oncologist, Elizabeth Plimack, M.D., M.S., had in an immunotherapy trial at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“The trial sounded really promising, so I agreed to do it,” Messinger says of the ongoing phase 1 study, which is considering the best dosing for the immunotherapy Opdivo (nivolumab) when it’s combined with targeted drugs Sutent (sunitinib) or Votrient (pazopanib), as well as the effectiveness of Opdivo given with either Sutent, Votrient or another immunotherapy, Yervoy (ipilimumab). Two- and-a-half years later, Messinger is still taking her immunotherapy regimen.

Yervoy is an immune checkpoint inhibitor, which blocks the protein CTLA-4 on T cells. The job of CTLA-4 is to help hold the body’s immune system in check; blocking its activity frees up a patient’s immune system to work more powerfully to kill cancer cells. Opdivo is another checkpoint inhibitor that works on the same principle, but targets a different protein, PD-1. These drugs can slow tumor growth or even shrink tumors.

Messinger, who goes to the clinic for assessment and treatment every two weeks, is experiencing a few side effects from her treatment, but nothing that makes her feel she needs to discontinue it.

“I’m really tired and, just lately, my joints and bones have started hurting. They don’t know if it’s the nivo or because I’m 60,” she says. “I get nauseated now and then, but for the most part, it’s really not been a bad ride at all.”

Both Yervoy and Opdivo have been approved for at least a couple of years to treat other cancers, but it was only recently that Opdivo was given the green light by the U.S. Food and Drug Administration (FDA) for use in patients with advanced RCC. That happened in November 2015, based on findings from a phase 3 trial, which showed longer overall survival and fewer serious side effects with Opdivo than with another newer treatment, the targeted drug Afinitor (everolimus). Opdivo can cause side effects including fatigue, itching, rash, upper respiratory problems, swelling of the hands and feet, gastrointestinal disturbances, muscle pain, fever, and abdominal, chest or joint pain.

“This drug works by stimulating the body’s immune system in a much more specific fashion than previous generations of such treatments, to elicit an immune response,” says Sumanta Kumar Pal, M.D., assistant clinical professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “When you look at the older classes of immune- based treatments, like IL-2 (interleukin-2) and interferon, these were incredibly toxic. There were many toxicities that ultimately might lead to death. This is far different with the targeted, immune- based therapies that we have now in the clinic. By and large, I’ve found that patients are able to maintain their quality of life. It always helps to have tight oversight by a physician who is knowledgeable of these medications. If you do have that, then certainly, you can still enjoy excellent quality of life while extending survival.”

It’s an improvement that’s a sign of the times. The treatment landscape for advanced RCC has changed drastically over the past few years, with several targeted drugs that are not immunotherapies also approved by the FDA. These include Cabometyx (cabozantinib) and Lenvima (lenvatinib), which target and disable cell enzymes known as tyrosine kinases that help drive some cancers. There’s also a regimen that combines two kinase inhibitors, Afinitor and Lenvima. As a group, these therapies have the potential to further reduce RCC’s already dropping mortality rate.

A TARGETED APPROACH

Until about 10 years ago, a diagnosis of kidney cancer was grim. If the cancer was caught early enough, surgery to remove the kidney and tumor may have been sufficient treatment, but anything beyond complete removal rarely had a good outcome. Unfortunately, detecting early kidney cancer, which tends to be asymptomatic, is not easy.

“We don’t have any screening techniques for kidney cancer as it stands now,” says Pal. “With kidney cancer, often times we catch it at a much more advanced stage because of the lack of appropriate screening.”

Traditional chemotherapies, called cytotoxic chemotherapies, can sometimes be successful in treating other cancers, such as breast cancer or lung cancer, but are not effective for kidney cancer.

For a while, biological therapy, or immunotherapy, was the only hope for many patients with advanced RCC. Researchers found in 1985 that interleukin-2 (IL-2) could use a patient’s own immune system to shrink tumors in the kidney. The FDA approved its use to treat advanced kidney cancer in 1992. However, few patients responded well to the treatment, and the side effects were quite serious, often requiring patients to be admitted to intensive care units. While the treatment was potentially curative for those who responded to it, the drug produced responses in only about 10 percent of patients.

The newer targeted therapies, meanwhile, such as Cabometyx and Lenvima block cancer cells from getting the nutrition they need in order to develop new blood vessels and grow (angiogenesis), and/ or block proteins that help the cancer cells survive. “One of the principle molecules that we think drives kidney cancer growth is a molecule called VEGF,” Pal says. There are now, in practice, more than half a dozen drugs that target that particular molecule. Besides Cabometyx, these include Nexavar (sorafenib), Sutent and Avastin (bevacizumab). Nexavar was approved for treatment of advanced RCC in 2005, Sutent in 2006 and Avastin in 2009. In addition, VEGF inhibitors Votrient and Inlyta (axitinib) were approved in 2009 and 2012, respectively. “We also have two drugs that target a molecule that’s downstream from VEGF called mTOR,” Pal says; these are Torisel (temsirolimus) and Afinitor, approved in 2007 and 2009, respectively.

One of Pal’s patients, 65-year-old David Pasternak, a lawyer in Los Angeles, California, was diagnosed with advanced RCC in April 2014, after tumors were found in his lungs. Two months after his diagnosis, Pasternak entered a phase 1 clinical trial, taking Avastin and the new checkpoint inhibitor Tecentriq (atezolizumab) every three weeks. It’s one of a number of trials to combine targeted drugs with immunotherapies or with each other, a strategy experts believe may further improve the effectiveness of RCC treatment. “I was the first patient at City of Hope on this trial, and it was terrific for over a year,” Pasternak says. “The tumors in my lungs were shrinking, although recently they have been growing a little bit.” Pasternak has since been switched to Cabometyx.

The newest drug available to treat advanced RCC, Cabometyx targets not only VEGF, but a combination of other proteins at the cell surface that drive kidney cancer growth. Approved in 2016, as was Lenvima, Cabometyx got the green light based on results from the phase 3 METEOR trial, which compared it with Afinitor. The findings showed that Cabometyx offered patients longer progression-free survival. The most common side effects of Cabometyx include gastric system disturbances and fatigue. Lenvima’s approval was based on a phase 2 trial that compared Lenvima plus Afinitor, Lenvima alone and Afinitor alone. In this study, Lenvima plus Afinitor and Lenvima alone both resulted in longer progression-free survival than did Afinitor alone.

Lenvima can cause high blood pressure, diarrhea, joint pain, fatigue, nausea, mouth inflammation, headache, and swelling and/or pain in the hands and feet. Afinitor’s side effects can include nausea, vomiting, diarrhea or constipation, an unusual taste in the mouth, itching or skin rash, nosebleeds, mouth sores, high blood sugar, lung inflammation and headache and other cold symptoms. In the trial of Lenvima and Afinitor, both regimens containing Lenvima sparked more serious or severe side effects in patients, mainly diarrhea and the presence of extra protein in the urine, which can indicate kidney damage.

Pasternak says that his quality of life has remained positive while participating in the trial of Avastin and Tecentriq. “I have been working full-time, have had a full social life, almost completed a year as president of the California State Bar, and had much travel within the state of California this year, flying to northern California about 25 times,” he says.

WHICH DRUGS, IN WHICH ORDER?

The newer treatments were approved as second-line therapies, to be used for patients whose cancer had returned following treatment, or whose cancer did not respond to treatment. Cabometyx, Opdivo and Lenvima were each approved for patients who had previously received treatment with anti-angiogenics, such as Avastin. Afinitor was approved for use in patients whose cancer had returned or progressed after they take Sutent or Nexavar.

“Right now, we don’t necessarily know which factors drive benefit with one drug over the other,” Pal says. “I tend to favor cabozantinib in second-line treatment because, with this drug, it’s really the first time we’ve seen a benefit in this setting for progression-free survival, response rates and overall survival.”

According to Thomas E. Hutson, D.O., Pharm.D., director of the GU Oncology Program at the Charles A. Sammons Cancer Center at Baylor University Medical Center in Dallas, Texas, therapy with VEGF inhibitors (Sutent or Votrient) is what most people should get first. The COMPARES trial, published in the New England Journal of Medicine two years ago, compared Sutent versus Votrient and showed that Votrient was not superior to Sutent, so patients generally receive either drug as their first therapy, he says.

Afinitor is no longer the first choice for second-line treatment, Hutson notes, with better options being Opdivo, Cabometyx, Lenvima plus Afinitor, or Inlyta. “To be honest, you probably want to give all four of those therapies at some point,” he says. “What we don’t know is what the sequence should be. You can’t give them all second, so you have to choose, and we don’t have comparative trials that show us which is the best therapy. Unfortunately, we don’t really have the data yet to tell us, without a doubt, that one drug should be given over the other. I think we’re waiting on future trials to help guide us as to what the optimal order should be.”

Taking the precision medicine approach is also important, meaning that doctors should know which targetable mutations, if any, are driving a patient’s cancer, says Toni Choueiri, M.D., director of the Lank Center for Genitourinary Oncology and the Kidney Cancer Center at the Dana-Farber Cancer Institute in Boston, Massachusetts. Taking into account each patient’s variability (genes, environment and lifestyle) should also play a role in choosing treatment. “I look at drugs that are more tolerable. I look at the side effect profile of each drug and at the patients,” he explains. “If a patient has an established autoimmune disease on therapy, this person should not have novel immunotherapy. If you have a patient who struggled with severe hypertension and intolerable tyrosine kinase inhibitor side effects even after dose reduction, maybe I wouldn’t move to one that has a similar side effect profile.”

A BETTER QUALITY OF LIFE

Finding an effective treatment means also finding therapies that patients can take without impacting their quality of life so much that they will discontinue their regimen. This was a problem faced by many patients who were treated with IL-2, which could cause flu-like symptoms; rapid heartbeat; low blood pressure; swelling of the hands, face, and feet; and difficulty breathing, to name a few. IL-2 is given in the hospital, often in the intensive care unit, because all or nearly all patients experience serious side effects and may need medical support. A 2015 review that looked at a variety of studies done on the side effects of IL-2 indicated that low blood pressure was perhaps the most common side effect; one study found that it occurred in 92.6 percent of enrolled patients taking low-dose IL-2.

“The side effects associated with low-dose (720,000 IU/kg) intravenous treatment were not trivial,” the review states. “More than half of the treatment courses were discontinued due to intolerable side effects.” As a result, Hutson says, IL-2 has “fallen out of favor,” and is mostly not given to patients with advanced RCC anymore.

The side-effect profiles of the newer treatments are significantly less severe. For example, results of the phase 3 METEOR trial show that serious or severe side effects affected 39 percent of patients who took Cabometyx, and 40 percent who took Afinitor. Twelve percent of the first group stopped treatment, and 11 percent of the second group. The most common side effects from Cabometyx were diarrhea, fatigue, nausea and decreased appetite.

Messinger, for one, has been satisfied with her experience on the newer drugs. They’re allowing her to look forward, she says, to watching her grandchildren grow. “I have a new one on the way, and a 3-year-old,” she says. “I think I’ll be around awhile. I will keep fighting.”

Given the new research and what is coming down the pipeline, oncologists experienced in treating advanced RCC are encouraging patients like Messinger to be hopeful. “The future is actually bright,” Choueiri says.

“This is a positive thing in 2016 compared to what we had in 2005 and even in 2010,” Choueiri says. “Patient survival is more prolonged. People are living two, three and four times longer. The future is brighter and brighter.”