In A First, Kidney Cancer Drug Extends Survival

The NEJM has published two papers on kidney cancer treatment to coincide with their presentation at the European Cancer Congress in Vienna. While neither study yields fantastic results, each demonstrates a significant benefit for a new drug in patients with advanced, refractory renal cell (kidney) tumors.

In one trial, an immune checkpoint antibody, nivolumab (Opdivo), improved overall survival; it is the first phase 3 study to demonstrate such an advantage in advanced kidney cancer. The drug also had a positive effect on patients' quality of life. In the other analysis, a pill called cabozantinib (Cometriq) hindered kidney tumor growth. An accompanying editorial calls the benefit of each drug "unequivocal" and also points to limitations of these new meds and concern about costs.

Taken together, the findings raise many possibilities – and questions about strategy, and expense – for testing and prescribing new small drugs and immune-targeting antibodies to patients with kidney and, potentially, other advanced cancer forms.

The METEOR study compares two pills, cabozantinib and everolimus in 658 patients with heavily-pretreated renal cell (kidney) cancer, tumors that progressed after therapy targeting VEGFR. The open-label randomized trial demonstrated a near-doubling of progression free survival in patients receiving cabozantinib, from 3.8 to 7.4 months. This study was funded by Exelixis Inc, the company manufactures cabozantinib as Cometriq. This small-molecule, oral drug works by blocking VEGFR and other tyrosine kinases including Met and Axl. Previously, it has been FDA-approved for use in medullary thyroid cancer.

The CheckMate 025 study compares nivolumab, a PD-1 blocking-antibody and the oral drug, everolimus. This antibody is among a new class of drugs called immune checkpoint inhibitors. The trial includes 821 adults with advanced renal cancer of the clear cell type (the most common form). The median overall survival among participants randomized to receive nivolumab was just over 2 years, at 25.0 months; for those receiving everolimus, it was 19.6 months. Yet the total objective response rate to nivolumab was only 25%. Complete responses were rare (1%). This study was supported by Bristol-Myers Squibb (BMS), the company that sells nivolumab as Opdivo.

In each of the new reports, the new drug was compared to the same: everolimus given at a standard dose of 10 mg by mouth, daily. This Novartis drug, sold as Afinitor, is FDA-approved for treatment of advanced kidney cancer and a few other malignancies. In general, the measurable response rate to this mTOR inhibitor is quite low in patients with advanced disease that's resistant to other targeted treatments, in the range of 5% or less, and toxicity significant. Reported side effects include rash and other allergic reactions, chest pain and difficult breathing, fever, sores, jaundice, bleeding and other problems.

Based on lab studies reported so far, nivolumab-responsiveness could not be predicted based on pathological features of the tumors, such as levels of PDL-1. The antibody was given by intravenous infusion every other week. Toxicity was also better in the nivolumab arm: grade 3 or 4 adverse effects were noted in 19% of that group, compared with 37% of the everolimus recipients. No deaths were attributed to nivolumab. Side effects from nivolumab, as reported in this trial, included fatigue, nausea and itching. Serious effects were mainly related to low blood counts, such as anemia.

Randomization in the CheckMate 025 trial was stopped early in July, 2015, upon an interim analysis due to the observed survival benefit of nivolumab. Quality of life, as assessed by the FKSI-DRS questionnaire was superior for nivolumab group, too.

"These are exciting results," said Dr. Robert Motzer. He is a kidney cancer specialist at Memorial Sloan Cancer Center in New York and a principal investigator in both studies. He has received research funding, through Memorial Sloan Kettering Cancer Center, from both BMS and Exelixis. He holds consultancy positions with Pfizer, Novartis and Eisai Inc.

"One of the challenges in kidney cancer is that patients develop resistance to treatment," Motzer said. "There is a need for new medications."

The Nivolumab study is the first to prove that immune checkpoint inhibitors help patients with kidney cancer, Motzer said. "There was considerably less toxicity with this drug than with everolimus. The improved overall survival, durable responses, and favorable safety profile for Nivolumab is what really stands out."

For cabozantinib, what's evident so far is improved progression free survival. The METEOR study, also an open-label phase 3 analysis, showed a near-doubling of time for the tumor to progress, of 7.4 months, compared with the standard everolimus treatment (3.8 months). The total objective response rate reported for cabozantinib was 21%, and that for everolimus 5%. (In 2009, the FDA approved everolimus for treatment of kidney cancer that is unresponsive to either of two other targeted drug; in that approval, the FDA cites a response rate as low as 2% for everolimus.) Serious (grade 3 or higher) toxicity from cabozantinib, as reported in the study, included high blood pressure, diarrhea and tiredness.

"The benefit of cabozantinib may be greater than these numbers suggest," Motzer said. "The overall survival data are not yet mature," he said. "There may be durable responses, but we don't know that yet." The METEOR study, comparing cabozantinib to everolimus, was designed to evaluate patients with very resistant tumors, he added. "It could be that it would help more patients, possibly in combination with other drugs, and with earlier and less resistant disease."

Until now, therapy for advanced kidney (renal cell) cancer has been limited, Motzer said. There are most of a dozen FDA-approved medications for advanced disease. The newer drugs predominantly fall into two groups: mTOR inhibitors, like everolimus and temsirolimus; and targeted drugs that generally take aim at any of several VEGF receptors and other signaling molecules, proteins involved in cancer cell growth, like sunitinib and pazopanib, Motzer indicated.

"There's a long history of treating kidney cancer with immune drugs," he said. "But Interferon and IL-2 only helped a small proportion of patients," he considered.

I asked Motzer about the toxicity of cabozantinib, which according to the report led to dose reductions in 60% of patients assigned to that arm of the study. "It's manageable," he said. "We still saw benefit after physicians lowered the doses," he observed. On this study of 658 patients, 9% of patients randomized to get cabozantinib discontinued it entirely, as compared to 10% of the everolimus group.

***

"This is the first time a phase 3 study has ever shown a survival benefit in treatment of patients with advanced kidney cancer," said Dr. Padmanee Sharma. She's an oncologist with a PhD in immunology who specializes in genitourinary cancers like those of the bladder, kidney and prostate. She and her husband, immunologist Jim Allison, are two directors of the immunotherapy platform within the Moon Shots program at MD Anderson Cancer Center in Houston. She is the co-principal investigator and corresponding author on the NEJM nivolumab study.

I met Sharma recently in New York City. We discussed immune drugs, including nivolumab, for renal cell cancer, and ongoing laboratory studies that might identify, or anticipate, which patients who are likely to respond to this drug. She provided additional information in subsequent emails. Sharma has received consulting fees from Bristol-Myers Squibb, Amgen, AstraZeneca/MedImmune and Glaxo-SmithKline. She has advised Jounce Therapeutics and owns stock in that company.

"This drug gives hope to patients with renal cell cancer," she said. "These are not like the drugs cancer patients used to get," she said. "We observed both improved survival and improved quality of life for patients who received nivolumab." The toxicity profile is favorable, she emphasized. "You're not in bed, losing your hair, throwing up."

"This study is good news for cancer patients, and not just for those with kidney cancer." There are many upcoming immune treatments, and combinations we should try," Sharma said. "For a long time cancer patients thought that's it, my life is over," she said. "We want to make cancer a chronic disease. For many people now, we can keep their cancer in check."

***

There will be over 61,000 U.S. kidney cancer diagnoses this year in the United States, and approximately 338,000 worldwide. The U.S. incidence appears to be rising since 1992. According to the NCI, kidney cancer is significantly more common in men than in women, and is found most often between the ages of 50 and 70 years. (Childhood kidney cancers do occur, and were not studied in either of these reports.) In the U.S., these cancers disproportionately affect blacks, American Indian and Alaska Native populations.

A few known genetic changes can dispose a person to developing kidney cancer, and may be inherited. The most studied of these syndromes involve variants in the tumor suppressor Von Hippel-Lindau (VHL) gene.

***

"I'm happy because I'm alive," said Peggy Zuckerman in a phone interview. Now at age 66, she lives in the Los Angeles area, advocates and writes about kidney cancer and experiences as a patient. She receives speaking fees from Prometheus Labs (Novartis), the company that manufactures Proleukin (IL-2).

In a phone interview, Zuckerman told me she had a large, stage 4 kidney cancer found, after diagnostic delays, in March 2004. She had so many lung metastases "the doctors couldn't count." She underwent a radical nephrectomy (kidney removal) at the Mayo Clinic. Since then, most of her care has been through UCLA in Los Angeles. After a brief course on an experimental angiogenesis inhibitor, anti-thrombospondin drug, the lung metastases appeared to be growing. In the summer of 2004, she began a trial of high-dose IL-2.

"If it weren't for high-dose interleukin 2, I'd be dead," she told me. "I had a remarkable response." She received doses every 8 hours, in the hospital, every other week for approximately two months, from approximately July to September, 2004. "The tumors were shrinking. On the x-ray, the lung fields were clearing, like little snowflakes disappearing," she said. The doctors perceived she had at least a partial response.

"By February 2005, essentially 5 months after the last dose of the IL-2, the lungs were clear except for two tiny spots," Zuckerman said. Her doctors think those are inactive. Since then – over 10 years ago – she has received no treatment for kidney cancer.

"I think it's important for patients to be aware of all their treatment options," Zuckerman said. "Everyone should see a specialist," she said. "By that I mean a medical oncologist who treats kidney cancer," she clarified. "You need a doctor who can determine exactly what kind of kidney cancer you have. If you're 46 or younger, you should have genomic testing," she added.

Zuckerman recommends that patients talk to other patients. She, originally from North Dakota, taught elementary school years ago and has recently earned a certificate from UCLA in patient advocacy.

"It's difficult to compare one drug to another," Zuckerman said. "You have to look at the statistics, trial design, and recognize that most of these drugs are simply holding action," she said in discussing targeted drugs previously reported. "They may cause some shrinkage, for which patients are incredibly grateful. But many are devastated when they find out months later, after trying a new drug, that their tumor is no longer responding."

"We'd be thrilled to have another good tool in the system," Zuckerman said when I mentioned the possibility of effective new drugs for kidney cancer. "I'm acutely aware that I was lucky," she said. "The reality is most patients develop resistance to new drugs," she cautioned. "We need a plan B and then a plan C."

***

I asked Sharma what renders some kidney cancer responsive to immune treatments. For over 25 years, oncologists have used interleukin-2 (IL-2) and a few other immune drugs such as interferon. This immune effect, including rare reports of spontaneous regression of kidney cancer, has been long-known among physicians.

As mentioned in the NEJM editorial accompanying the new reports, almost one in four advanced kidney cancer patients respond to interleukin-2, and a smaller fraction respond completely. A 2005 paper reviews the largest phase 2 trial of these treatments, which back then were considered costly and toxic.

"Probably there is an underlying immune response that is stronger in some patients. But we don't yet know what that is," Sharma said.

"IL-2 has been around for so long," Sharma said. "It has to be given in an ICU setting. That is difficult for a lot of patients." The risk-to-benefit ratio for nivolumab is much better than for interleukin-2, she added.

In a planned earlier-phase trial, she and co-investigators will examine the combination of two checkpoint inhibitors, ipilimumab (Yervoy) and nivolumab in a small cohort of men with advanced prostate cancer. "I don't know what the cost is," she told me. Both drugs are manufactured by Bristol-Myers Squibb, which will sponsor that trial.

***

"Taken together, these studies mark the beginning of an era for people with kidney cancer," Motzer said. "We're seeing an amazing expansion of the armamentarium, of anti-cancer agents that might help patients."

Motzer referred to broad interest in combining these new drugs. He mentioned an international trial combining ipilimumab (Yervoy) and nivolumab (Opdivo), two distinct immune checkpoint inhibitors (CTLA-4 and PD-1). Each is manufactured by BMS. "That's almost reached accrual," he said.

There's considerable interest in combining these immune-blocking antibodies with oral, small-molecule enzyme inhibitors, Motzer said. "The possibility of combining VEGF inhibitors and checkpoint inhibitors is enticing. They both have activity," he said. "It's possible that the VEGF therapy will cause a lot of cell destruction that would activate the checkpoint inhibitor."

"This is not the end of research in terms of these classes of compounds. It's a big step. Years back, with development of the currently available VEGF-targeted drugs, it wasn't cleared to me that there'd be more progress in kidney cancer," Motzer said. "This opens the door to many more options for patients."

*update 9/26/15 2PM