Only 10 to 15 percent of patients with metastatic kidney cancer respond to standard immunotherapy, and there are no standard effective therapies for patients who fail or can't tolerate standard immunotherapy. In this study, however, 42 percent (21 of 50) of patients had their tumors shrink at least 25 percent within the first 12 weeks. Six of those patients had a reduction of 50 percent or more.
Another 26 percent (13 patients) had their tumors stabilize within 25 percent of pre-treatment size. The remaining 32 percent left the study because of progressive disease or adverse effects, such as a painful rash or diarrhea.
"This is the most exciting thing in oncology since Gleevec," said the study's lead investigator, Mark Ratain, M.D., professor of medicine and chief of clinical pharmacology at the University of Chicago. "All but one of the kidney cancer patients in this study had advanced disease that did not respond to at least one previous systemic treatment, yet almost half of them had a rapid and very encouraging response to this drug."
The study also served to validate a new approach to phase II trial design. Most phase II trials test the effects of a new drug on patients with a specific disease, such as colon cancer, and limit the goal to determining the percentage of patients who have at least a 50% reduction in tumor size. This study, a "randomized discontinuation trial," enrolled patients with many different tumor types for 12 weeks, then randomized patients with stable disease to placebo vs. continued treatment.
"This approach allows us to test a new drug for effects in many tumor types and then concentrate on patients most likely to benefit," said Ratain, who designed the study, only the second of its kind. "It allows us to learn broadly about a drug's activity, including assessment of disease stabilization. The standard phase II design can efficiently prove that a drug is inactive, whereas this design can efficiently prove that a drug delays tumor progression."
In this trial, patients who have a good initial response, tumor shrinkage of at least 25 percent, continue on the drug. Those with stable disease, defined as tumor shrinkage or growth less than 25 percent, are randomized to receive either the drug or a placebo for the next 12 weeks. Those with tumors that grow 25 percent or more are removed from the study.
The novel design may have rescued this promising drug from obscurity. It was originally expected to play a role in colon cancer treatment. It had little effect, however, in 131 colon cancer patients and might have been abandoned if its effects in renal cell cancer, the most common form of kidney cancer, had not emerged.
"This is by far the most exciting thing in kidney cancer right now," said kidney cancer specialist Walter Stadler, MD, associate professor of medicine at the University of Chicago, "but there's still a lot we don't know, like the long-term effects, possible late toxicity, how it affects survival or its impact on quality of life."
The trial began in October of 2002. Doctors at the University of Chicago treated the first renal cell cancer patient one month later, on November 12, 2002. After 12 weeks he had stable disease. The second patient began treatment on November 27. He had dramatic tumor shrinkage. Patient three had similar results. It soon became apparent that many patients with kidney cancer were responding, and the study filled up five times faster than expected.
"Because of this drug I'm still doing well," says study participant Donald Jeffers of Plainfield, IL. Jeffers had a cancerous kidney removed in 1981 but more aggressive cancer returned at multiple sites in 1995. An out-of-state specialist told him to "go home and get your affairs in order," but his family physician connected him with researchers at Chicago.
His tumors initially responded to immune therapy with IL-2 -- "very nasty," he recalls, "but it helped for a while." When that no longer worked, he took part in a series of trial therapies, none of which made much difference.
"I've had the ports, the pouch and the pump," says Jeffers. "I've had surgery, radiation and gene therapy. So when they put me on four little pills a day I didn't expect much. I didn't even have side effects, except maybe a little tenderness on my tongue and some hari loss. It's like taking M&Ms. So I thought I was getting a placebo. But after three months, my CT scan showed the tumor was only half as big."
"You can't judge from anecdotes," cautions Bill Bro, director of the Kidney Cancer Association, based in Evanston, IL, "but if the number of phone calls or the willingness to travel for treatment is any measure, then this is an exciting development."
By June of 2003, the first 41 kidney cancer patients had been treated. Word-of-mouth reports of frequent responses soon attracted more patients. By the end of October, 112 kidney cancer patients had begun the therapy and 50 had been evaluated.
"This drug has come to dominate talk in kidney cancer circles," said Stadler. "It has major buzz."
On October 25, 2003, Onyx Pharmaceuticals of Richmond, CA, and partner Bayer Pharmaceuticals Corporation announced the beginning of a phase III trial comparing Bay 43-9006 to placebo with plans to enroll 800 kidney cancer patients worldwide. Drug makers commonly use phase III data, comparing an investigational drug against standard therapy, to persuade the Food and Drug Administration to approve a new drug.
In this case, however, such promising phase II results may force the company (and FDA) to redesign that trial. Median survival for patients with advanced metastatic kidney cancer is less than one year. Response to standard chemotherapy is less than ten percent and to immunotherapy around 15 percent, but with considerable toxicity. Faced with those dismal statistics, Onyx and Bayer now have a drug producing a preliminary response rate of 42 percent in patients with advanced cancer who had already failed standard or investigational therapy.
"This drug is too good for the phase III trial as designed," said Ratain. "With results like this it will be ethically challenging to assign half the patients to standard therapy, much less to placebo."
He has encouraged the makers to extend the phase II trial, which is still accruing patients, and to seek FDA approval based on those results compared to historical controls, or to design a new phase III trial.
"It's a difficult issue," adds Stadler. "When you've got something exciting for a lethal disease like advanced cancer, how much evidence do you need?"
"When I'm face-to-face with patients," he adds, "they want access to this drug. When I stand up in front of my colleagues they want data. We simply don't have that just yet. We need more patients, longer-term results and we especially need to see what happens to the group that got randomized."
Meanwhile, even the buzz is encouraging. "When I had my first CT scan last summer I didn't have much hope," recalled Jeffers, "didn't expect much. Then they told me my tumor had shrunk by 50 percent. I've got my second scan next week, and this time I've got hope."
About 190,000 people worldwide are diagnosed with kidney cancer each year, including about 32,000 in the United States. About half of U.S. patients are eligible for surgical removal of the cancerous kidney, but if the tumor has already spread beyond the kidney, surgery is less effective. About 12,000 U.S. patients die each year.
BAY 43-9006, is believed to inhibit an enzyme, known as Raf kinase, which regulates tumor-cell proliferation and may also play a role in the growth of new blood vessels to feed the tumor.
Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals funded this clinical study. Additional researchers include Keith Flaherty and Peter O'Dwyer of the University of Pennsylvania, Philadelphia; Stan Kaye of Royal Marsden Hospital, Sutton, UK; Amita Patniak of the Cancer Therapy and Research Center, San Antonio; Tim Eisen of the Royal Marsden NHS Trust, London; and Henry Xiong of MD Anderson Cancer Center, Houston.