Interim results from a phase II trial of an investigational drug known as BAY 43-9006 or sorafenib demonstrate a significant and lasting benefit for a subset of patients with advanced renal cell cancer, researchers from the University of Chicago and four other centers report at the American Society of Clinical Oncology annual meeting in New Orleans, June 5.
This presentation provides the first evidence that this drug can produce durable responses. Of the 37 (out of 106) patients who had at least 25 percent tumor shrinkage in the first 12 weeks, 88 percent were progression-free after 24 weeks. For this group, the median time to progression was 48 weeks -- or nearly one year.
"This drug appears to cause tumor regression in a subset of patients, to maintain those regressions and to do it with limited toxicity," said the study's lead investigator, Mark Ratain, M.D., professor of medicine and chief of clinical pharmacology at the University of Chicago. "These patients had a very encouraging response to this drug even though most of them had advanced disease that had not responded to at least one and sometimes several previous systemic treatments."
In this study, 35 percent of patients (37 of 106) had their tumors shrink at least 25 percent within the first 12 weeks. Thirteen of those patients had more than a 50 percent decrease at 12 weeks. All 37 continued to take the drug. "There is not a discrete cutpoint at the 50 percent mark," noted Ratain. "This drug appears to be active in a large proportion of treated patients."
Another 42 percent (45 patients) had their tumors stabilize within 25 percent of pre-treatment size, which met the criteria for randomization to drug or placebo. Thirty-eight of these patients participated in the randomized portion of the trial.
Thirty-one of the 106 patients eventually left the study because of progressive disease, adverse effects or other reasons.
These results, although preliminary and difficult to compare, have attracted a lot of attention among physicians and patients considering standard and other investigational therapies for kidney cancer. Only 10 to 15 percent of patients with metastatic kidney cancer respond to standard immunotherapy, which can be very toxic. In this study, about 15 percent of patients had a comparable "partial response," but nearly two-thirds of the patients had stable disease when measured at 12 weeks and for many of them this persisted for months.
There are no standard effective therapies for patients who fail or can't tolerate immunotherapy. The study also served to evaluate two new concepts in phase II oncology 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 percent reduction in tumor size.
This study, however, allowed enrollment of patients with a wide variety of solid tumors. In addition, it was a "randomized discontinuation trial." It began with an initial treatment course of 12 weeks. Then patients were sorted according to their initial response. Those with tumor shrinkage of at least 25 percent continue on the drug.
Those with stable disease -- tumor shrinkage or growth less than 25 percent -- were randomized to receive either the drug or a placebo. The randomized portion of the trial has not yet been unblinded, although that is anticipated to occur in the next three to four months.
"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 and permits screening for antitumor activity in a broad spectrum of tumors. The value of this flexibility is evident from the high response rate in kidney cancer learned from a trial designed for colorectal cancer."
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 138 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. It also appears to be active in sarcoma and thyroid cancer.
"This is clearly a major advance for kidney cancer patients," said kidney cancer specialist and study co-author 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, and its impact on quality of life."
The trial began at five centers 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 renal cell cancer 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, accruing 484 patients with various tumor types within 16 months.
The data presented at ASCO include 106 kidney cancer patients who enrolled in the trial between November 2002 and September 2003. Today's presentation follows their progress up to May 3, 2004. Another 97 patients entered the study since last November and are still being evaluated, but were not included in this analysis.
The early results were sufficiently encouraging for Onyx Pharmaceuticals of Richmond, CA, and partner Bayer Pharmaceuticals Corporation to announce the beginning of a phase III trial of Bay 43-9006 on October 25, 2003. This trial will enroll 800 kidney cancer patients.
BAY 43-9006 was developed against Raf kinase, which regulates tumor-cell proliferation and may also play a role in the growth of new blood vessels to feed the tumor. However, recent data demonstrate that the drug has other targets, including one of the receptors of vascular endothelial growth factor. Although it is clear that this targeted therapy hits a target -- based on its remarkable activity in kidney cancer -- it is not clear which target's inhibition is critical to the drug's activity.
The side effects of the drug have been relatively mild. The most common serious adverse effects were hypertension and a rash on the hands and feet. Only five percent of patients required a dose reduction and 18 percent had to interrupt the dose because of side effects.
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.
