DR. THEODORESCU: Thank you very much. Can we have the panelists up?

DR. THOMPSON: While the panel is assembling, let me just comment that in the next session, many of our speakers could not come because of the weather, so there are only going to be two talks, and then some discussion which Paul Lang will moderate. We should be back on time for the late-breaking abstract session.

DR. THEODORESCU: Any questions from the floor?

PARTICIPANT: With respect to the last talk on progressive renal cell carcinoma, most of those people that are put on these very specific signal transduction agents are people that have demonstrated progression. Yet there is a placebo arm. How is that justified? I don't understand. We recognize that there may be a time period where this stuff can stabilize, but I still don't understand having by definition, coming into the trial by progression, how there can be a placebo trial. Or would you like to be the person that is put on placebo if you had these certain circumstances?

DR. STADLER: The answer is yes, I would. The reason for it is as follows. Progression is defined over an arbitrary and variable period of time prior to entry into the clinical trial. Natural history of the disease is very variable. When a disease is stable for a relatively short period of time, 12 weeks, 16 weeks, one does not know whether that is because of or despite the drug that is being administered. I think both the treating physician, the oncologist as well as the patients feel that way.

Now, if the drugs are completely and totally benign, I think that yes, one could argue, who cares. But these drugs are not benign. We know some of the toxicities, but there may be other unknown toxicities that could be serious. So I think these kind of trials are important and necessary.

And validation that this is important is actually from the patient. The patients entered the trial. Patients can vote with their feet, and they voted with their feet. They are coming, and they have no objections, and the patient advocacy groups have no objections to these trials.

So I think that is the answer. Interestingly, a lot of these placebo controlled trials, I think we have to consider the data, we have to consider these things, we have to get the patient's input. But interestingly, sometimes doctors are more uncomfortable than patients.

DR. THEODORESCU: I have a question for the panel. One of the things that strikes me is that we have an enormous number of these new drugs coming on line, and one of the problems I see is -- or maybe it isn't a problem -- how are we going to be able to prioritize you for going into patients? Any thoughts?

DR. LINEHAN: There are a number of ways to think about it. Once, you've got preclinical models, you have the laboratory, you have xenograph models, this, that and the other. I think that is one way.

I think you actually raise a bigger question, and something I have raised in the past. People say there may be some interest in this. In a way, take kidney cancer; we know there are about 32,000 cases in this country each year. We know there are 12,000 deaths. We know pretty much the people who work on this in clinical trials. Why don't we consider doing what the pediatric oncologists do, that is, having one group of people working together, a little bit of an industrial plan for this.

If we say we only have one goal, and that is coming up with an agent that makes these tumors small in our patients, this might get there faster and quicker, and also might help answer that issue.

DR. THEODORESCU: I think that is important, because improving preclinical models, whether we are using transgenics, et cetera, but we are working on the patients, and also surrogate end points so we can filter these things quickly, and even perhaps do a modification of phase three trials with novel markers.

DR. STADLER: Let me comment on that. I'm not sure we need a Manhattan Project necessarily, but I do think we need to put more of these patients on clinical trials. We know a lot more how to divide the patients. Marston has clearly described the different types of kidney cancer. We ought to have clinical trials for those different types, not just put everybody in arbitrarily.

He pointed out, 12,000 patients a year. If ten percent go in clinical trials, that is 1200 patients a year. That is a lot of studies, if you can do it with just ten percent of patients.

PARTICIPANT: Quick question. That is histology on these trials?

DR. STADLER: Most of them are clear. From the metastatic standpoint, we looked at about 95 percent of the patients with metastatic disease, have clear cell histology.

PARTICIPANT: This is a question to Dr. Bartsch. When we looked at EGF as well as interleukin-6, activating androgen receptors, it is well known that androgen receptors can be activated independent of androgens by their ligands. Have you explored the possibility that these molecules can actually bypass the androgen receptor, in other words, can activate the cells independent of androgen receptors?

This may be clinically relevant, because just knocking out the androgen receptors with antisense and so on may not necessarily work, because some of these molecules can actually work independent of androgen receptors.

DR. BARTSCH: Actually, we have not done this experiment. But that is a very good question.

DR. WANG: I can probably comment on that. I know some work by Charles Sawyer at UCLA which has actually shown that low levels of androgen are needed, even in these settings where there is stimulation through other pathways, that talk together with it. But I think it actually is necessary for most cases, but I can imagine cases where mutations -- maybe where it is not necessary.

PARTICIPANT: We work on progression to androgen independence, and we have identified transduction molecules which can actually make androgen insensitive cells respond to androgens again. But this seems to work independent of androgen receptors. So you're right, there are a lot of other things going on there.

DR. BARTSCH: But we have shown on one slide, in the xenographs of the LNCAP lung ablated cells, the only environment which causes not growing the tumor was testosterone.

DR. THEODORESCU: We have time maybe for one more question.

PARTICIPANT: For Walter Marston. Historically, renal cell treatments have been primarily immunotherapy. As the targeted therapies evolve, what will happen to the immunotherapy? Will there still be some sort of synergistic effect with immunotherapy, or will it fade away?

DR. LINEHAN: If you want my opinion, number one, nobody knows. Number two, there have been a lot of advances in immunotherapy, and we'll see. Today the current FDA approved drug, for metastatic kidney cancer is interleukin-2. At least at the NCI there is a ten percent complete response, and in the most recent data, 11 percent partial response. Those responses are doable. The ones who have CRs, probably 95 percent at ten years. So I think that is an agent with proven efficacy in people.

If you want to know my personal bias, it wouldn't surprise me if we wouldn't see a combination of approaches in the future, potentially immunologic approach, molecular therapeutic approach. I personally haven't thought that far ahead, but that is what I would bet.

DR. THEODORESCU: Thanks very much.

DR. LINEHAN: Thank you very much, Dan, for running a great session. I am just completely blown away, as I am every year, by the sophistication of the work in our field, and the promise for the future.

Next we are going to do something a little tangible about the promise for the future. We think that one of the most important parts of this meeting, one of the most important participants in this meeting, are of course young people. This afternoon we have their meeting.

But the other thing that we are always so happy about is that these people come and bring posters and present them. We are going to work better on the poster sessions every year that we tinker with that a little bit. Next year will be better. But we are very happy to give the poster session awards for these posters that were presented yesterday.

Our three presenters, and I talked to them last night, I know they had an impossible job picking the best ones here, are Michael Gong, John Phillips and Christian Pavlovich . The third one will be Daniel Cohen, poster number 12, combination therapy with plasma beta two glycoprotein.

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