Urologic Oncology

SLIDES & TRANSCRIPTS
Saturday, December 6, 2003

Molecular Targeted Therapies in RCC

Walter Stadler, M.D.

Slide 1:

I owe a great thanks to a number of people, most importantly to the SUO for inviting me here today. I think it is prescient that the name of the society is the Society of Urologic Oncology, and not the Society of Oncologic Urologists. We really are oncologists, and it doesn't really matter what modality we happen to use to attack these diseases.

I would also like to thank Marston specifically for that nice introduction that he gave on this last talk, which makes my job that much easier, in describing some of the work that we have been doing in clinical trials with these agents.

Slide 2:

I think one of the most exciting things that has happened for metastatic kidney cancer is the identification of a number of receptor tyrosine kinase inhibitors. Marston has described some of the receptor tyrosine kinases, and importantly, there is a large number of these inhibitors that have been identified.

Many of these drugs have multiple potential targets, and they are dirty drugs. One of the things that we have learned over the last year or two is that dirty drugs may actually be good drugs rather than these very highly specific drugs that many of us have been seeking. These drugs may have both anti-tumor as well as anti-angiogenic activity, and there are at least three drugs that have interesting preliminary data in kidney cancer, PTK-787, a drug from Beyer that we worked with extensively, and a Sugen drug, 11248, importantly many others on preclinical and clinical development. I think this is only the beginning of an era.

Slide 3:

So in terms of this Bayer Beyer drug, it is a novel signal transduction inhibitor with potent activity against the RAF kinase. It was actually developed as a RAF kinase inhibitor. The RAF pathway as you have all heard is involved in tumor growth, but importantly, C - RAF also has a central role in endothelial cell signalling from both VEGF and EGF FDF stimulated pathways. This drug is also a direct inhibitor of both the VEGF and the PDGF receptors.

Slide 4:

The clinical trial that we conducted was a trial in which all patients received the drug of interest for 12 weeks. Those that had tumor growth then were taken off study, those that had tumor shrinkage -- and in this case we used a somewhat non-standard definition of at least 25 percent tumor shrinkage in bidimensional measurements, continued on the drug, and those with stable disease were then randomized in a double blind fashion to either continue the drug or to placebo, with the primary end point being the fraction of patients with stable disease at 24 weeks.

The reason for this trial design was that this drug was predicted and hypothesized to be a stabilizing agent, and because of the very highly variable valuable nature of metastatic disease and time to progression, we actually wanted to get at the stable disease end point.

Slide 5:

The eligibility. Interestingly, this trial was originally focused on colorectal cancers, based on the activity and importance of the CRAF oncogene in that disease, but we allowed other tumor types onto the study and had very broad eligibility criteria, and in essence the only exclusion were poor performance status, brain metastases or abnormal organ function.

Slide 6:

So this trial accrued very, very rapidly. It began approximately a year ago in collaboration with five institutions, and it is currently to all tumor types except renal cancer. As of October 6 for which I have the latest data, a total of 430 patients were accrued, of which 401 were treated, and we have data on 342 patients.

Slide 7:

For this audience, obviously the most interesting is the data on the kidney cancer patients. We have enrolled 50 of such patients. The slides change numbers as we go through it because the data is still accumulating, but the distribution and characteristics of these patients are fairly typical of the metastatic population. Importantly, 98 percent of the patients, essentially all of the patients except one, had prior therapy and prior systemic therapy, usually IL-2 and/or interferon.

Slide 8:

In the kidney cancer patients, of the 50 patients for which we have data, only 30 percent of those patients progressed within the first 12 weeks. We had 24 percent of patients who had at least a 25 percent shrinkage of their metastatic tumor mass, and approximately another 40 percent of patients or so who had stable disease and were randomized.

Slide 9:

This is the tumor shrinkage data on an individual basis on the first 34 patients. The patients in yellow had standard WHO criteria for response; that is about ten percent of the patients. Those patients in the green had minor tumor shrinkage, but continued on trial. The patients in blue had what was considered to be stable disease and were randomized to either continuing or discontinued therapy in the double blind manner.

Slide 10:

The therapy was fairly well tolerated. The major toxicities are in purple here, with hypertension being observed fairly commonly with serious hypertension, about five percent. Hand-foot syndrome was observed in grade three in eight percent of patients, and grade three diarrhea was observed in about eight percent.

Slide 11:

The most common toxicity was this rash. It probably doesn't project well at the end of the room, but it is a mild to moderate rash that occurred usually within the first two to three weeks, typically on the face and the thorax. This was somewhat itchy in some patients, but usually not bothersome, with the only effects being cosmoses and occasionally some hair loss in some patients.

Slide 12:

What we have been able to conclude so far is that this drug has acceptable toxicity profile for long term chronic administration, and there is significant anti-tumor activity in the renal cancer population. Evaluation of the randomized portion of the study will provide additional insight into the significance of the stable disease. Importantly from our standpoint, especially since a number of these disease stabilizing agents are now being evaluated, this trial design, this randomized discontinuation trial design, is a flexible design that is feasible and allows rapid accrual, and that is quite flexible.

Slide 13:

This is not the only drug. This is data that I have borrowed from Dan George, who is now down at Duke. Very similar data from the Novartis compound PGK-787. Once again, about seven percent of patients with a standard, in this case resist criteria, response, another 12 percent of patients who had a minor response, and a large proportion of patients who had stable disease. This was a single arm study in which the meaning of stable disease is a little more difficult to interpret.

Slide 14:

But what Dan George did do is, he used an MRI technique for looking at perfusion. He used a spin labelling technique, but has also used some more common dynamic contrast enhanced MRI. There is a nice correlation between the perfusion changes at one month and the time to tumor progression, giving some suggestion that these MRI methods may be a pharmacodynamic or perhaps even predictive marker for these type of agents.

Slide 15:

There are a number of questions with these new drugs. I have listed just a few of them here. Importantly, will these drugs improve survival and/or quality of life, are the available drugs equivalent and clinically cross resistant, how should these drugs be evaluated in the phase three setting, is there enough evidence of activity that a placebo control trial without crossover is acceptable, if crossover is allowed in a phase three study, is the difference in time to progression good enough for us, is it too soon to evaluate them in the adjuvant setting, and are there molecular imaging markers of drug associated benefits such as the MRI.

So I'll end there, and thank you once again for your attention.