National Editor

Figuring out how well several developing drugs for renal cancer stack up against each other was one purpose of a conference call with two experts, hosted by SG Cowen & Co., of New York, but it turned out clear lines were hard to draw.

In the spotlight were three compounds. The first was BAY 43-9006, the vascular endothelial growth factor (VEGF) inhibitor and RAF kinase from Richmond, Calif.-based Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp., a subsidiary of Bayer AG in Leverkusen, Germany. BAY 43-9006, granted fast-track status by the FDA, is in Phase III trials.

Another was SU011248, the multi-targeted tyrosine kinase inhibitor from Sugen Inc., a unit of Pharmacia Corp. (now part of New York-based Pfizer Inc.), for which renal cancer Phase II data will be among those presented at the American Society of Clinical Oncology meeting next month.

The third was high-profile Avastin (bevacizumab), a monoclonal antibody that also binds VEGF, which was approved in February for colorectal cancer and is in Phase III trials for kidney cancer. The CALGB 90206 Phase III trial will evaluate overall survival, time to disease progression and objective response rates in patients with advanced renal-cell carcinoma when treated with interferon alfa-2b, with or without Avastin.

"I think they all have some activity in renal cancer, but in terms of hierarchy, I don't think [the comparison is] possible," said Robert Motzer, associate chairman for clinical trials and attending physician at Memorial Sloan-Kettering Cancer Center in New York.

More willing to try it was Mark Ratain, associate director for clinical sciences at the University of Chicago Research Center.

"The Bayer-Onyx compound looks more active to me than Avastin," he said. "The Sugen-Pfizer compound is very active, and from what I've seen looks very similar to the Bayer-Onyx [drug]."

Ratain is the principal investigator in the ongoing BAY 43-9006 Phase III study. Asked whether data from the earlier Phase II trial could support a regulatory filing, he was definite again.

"My personal opinion, which is not the opinion of the company and not the opinion of the FDA - with those disclaimers, the answer is yes," he said, adding that "I can't tell you when we would know when [the ongoing Phase III] trial could be filed on, because I'm not involved in" filing.

Motzer pointed to a strong need for better first-line therapy. The usual approach to that particularly chemotherapy-resistant cancer is high doses of interleukin-2, given intravenously in an intensive-care setting, which gets about a 7 percent response rate.

"It has a lot of toxicity, it's difficult to give, it requires specialized sensors," he noted. Physicians have tried "less intense, cytokine-type therapies" at lower doses, he added, but "in general, all of those treatments are relatively unsatisfactory," with a median survival rate of about 10 months.

Complicating the development picture is the question of which standard is best to design clinical trials around - survival, progression-free survival or response rate.

"The way we measure antitumor effects classically has been with major response rate in Phase II trials, and in Phase III trials the classic endpoint has been overall survival," Motzer said. "Response rate with cytokines for the most part has not been correlated with overall survival," so progression-free survival has been introduced, even though there is "some debate as to how well that correlates with overall survival."

Analysts were encouraged, though, by a Phase II trial with BAY 43-9006. Conducted at five centers, the study consisted of two 12-week phases. The initial analysis included 41 patients with advanced and progressive renal-cell carcinoma who were evaluable after 12 weeks of treatment.

"The trial was designed to evaluate the ability of the drug to prevent progression in patients that had stable disease after an initial run-in of 12 weeks," Ratain said. "We were pretty comfortable the drug was active, which was what the trial was designed to assess."

In fact, he said, investigators were "surprised by the activity," although there "was no prominent evidence that the tumor was going to dramatically shrink further beyond the 12-week point."

About 32,000 new cases of renal-cell carcinoma are diagnosed each year and about 12,000 people die from the disease annually, according to data from the American Cancer Society.

"About 50 percent of all comers with renal cancers develop metastasis at one time or another," Motzer said.

"There's a rising incidence of the disease, and there's a trend toward earlier diagnosis based on improvements in imaging studies, but overall the population with metastatic disease has pretty much remained the same," he said.