SLIDES & TRANSCRIPTS
Friday, December 13, 2002

National Trials in Advanced RCC

Nicholas Vogelzang, M.D.

The standard treatment for kidney cancer is not either a nephrectomy looking for spontaneous regression, or chemotherapy. The mechanism by which the cancer is resistant to chemotherapy is unclear, but it's probably due to the xenobiotic transport proteins that are abundant on the surface of renal tubules.

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Chemotherapy shouldn't, however, be abandoned; 5-FU has some role. Gemcitabine as a nucleoside analogue may well be actively transported across the tubular epithelium, and the synergy between these two nucleoside analogues is real. We have seen objective responses in several sequence trials. And right now that trial, gemcitabine and 5-FU orally is in a phase II that just opened.

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The question of the role of interferon in this disease has been answered. It does have a modest, but real impact on median survival. These are two classic trials, both published in 1999. They both show an improvement in the median survival, and in the five-year survival rate. So interferon remains a very good standard.

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High dose versus low dose interleukin-2 remains an unknown. The median survival may not be changed, but as you can see, the dotted curve is the high dose arm. This is the cytokine working group. And it may well be that the impact of high dose IL-2 will only be in the five- and four-year beyond survivor group.

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I mentioned this earlier. There are different prognostic groupings.

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This is the Sloan-Kettering data looking at a good, intermediate, and poor risk patient. Note that the absence of nephrectomy is an immediate poor-risk factor.

Those factors have not been well taken into account in most of the national trials, and indeed, few of the national trials do anything like stratify by those prognostic factors.

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We have heard a lot today about the pathology, the clear cell with VHL mutations vs. the papillary with met mutations. Clear cell is probably going to be focused on for the anti-angiogenesis agents.

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The data for anti-angiogenesis is based upon the problem of disease stabilization. What does disease stabilization mean? Does it mean that your tumor is slowly growing, and you can't image it enough radiologically (certainly, PET scans are commonly negative in this disease)? Or does it mean that your therapy is prolonging the disease stabilization period?

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Well, the first trial to address this was Jim Yang's. I mentioned it earlier this morning. This is a very well designed and well thought through trial, using Bevacizumab or Avastin. And there are quite a number of other new small molecules in this same vein.

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The trial was a randomized, double blind, placebo-controlled, placebo vs. medium dose Bevacizumab or high dose Bevacizumab in only clear cell carcinoma. There was crossover allowed. The endpoint was time to progression and response rate. And the trial was closed early. Instead of 150, they had 132 patients.

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You will notice, as I showed you earlier this morning, the response rate of 10 percent tells us that this molecule is a real antibody. It does something to the biology of this disease. This response rate is not stunning, but it is a proof of principle.

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The time to progression curve I also showed you earlier is real.

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Now, the problem is, where do you go with this next? The only trial that I'm aware of that is on the national screen is a trial of interferon versus interferon with anti-VEGF. That trial is being planning in the CALGB. The capecitabine plus anti-VEGF is in phase II. I don't know of any other anti-VEGF trials. As I looked through the cancer.gov clinical trials website, there are no anti-VEGF trials among the 53 listed, so that's a problem.

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Small molecules inhibiting angiogenesis have been studied. This is a drug called CAI, also developed at the NIH. The mechanism is polymorphic, to say the least. And the phase I trial had some responses in renal cell, shown in the bottom there.

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This is a complex trial designed by my colleague Mark Reutan and Walter Statler in which we asked whether disease stabilization matters. And the trial, as you can see, is a run-in where everyone gets treated. After 16 weeks, patients who are responding continue, and if they are stable, they're randomized. So it's a really a randomized phase II trial. And we will then assess the response of those patients whose tumors are not growing, or not radiologically changing.

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The trial accrued like gangbusters - 374 patients in less than two years. It had a non-specific eligibility criteria, but it was closed, because it did not appear that CAI would be associated with a lower risk of disease progression.

The drug was not benign, in spite of this preclinical data, with neuropathy, nausea, and some fatigue. So it was hard to keep everyone on as long as they wanted to. But that's the sort of trial design that we're going to need.

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Thalidomide is one of these new ones as well. It is looking promising. It does lots of things in the angiogenesis and the cytokine cascade.

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There have been nine trials reported, 216 patients. The objective response rate is a stunning 5 percent. But again, it's 5 percent. It's not zero. Maybe like Rob said, it's similar to gamma interferon. The toxicities of neuropathy, constipation, somnolence, skin rash, form completion, and thrombosis are real.

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So here are those 53 clinical trials that are done nationally. We're not creative enough, folks. We've got to be more creative. Cytokine-based trials are 33 percent of all the trials. There is only 28 percent of the trials that are novel phase II's. That's 13. It's amazing. Vaccines and cellulars, you can see it. Allogeneic transplant, there are 7 approved trials on the NCI website. And there is a stunning 1 trial that is surgery. I should say shame on you. You need more trials in renal cancer on the surgical side.

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You already heard the update of the allo-transplant. I won't bore you with what Rick just said.

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Here is a slightly expanded database, including both the Childs data, our data, an MD Anderson abstract, Fred Applebaum's abstract, and two recently published papers. It's a small number still, 108 patients total reported; objective response rate is 30 percent. Graft-versus-host disease is about 60 percent.

And although Rick is being modest with his excellent treatment-related mortality rate of only 9 percent, everyone else has got a higher response of treatment-related mortality. So this is not yet ready for prime time.

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To conclude, here are at least as best I can tell, the total of the phase III trials. There is an EORTC trial of interferon with or without IL-2 and 5-FU. There is an ECOG trial of the mini-dose interferon, with or without thalidomide, 346 patients. I understand it's going very well.

There is the ACOSOG trial of radical versus renal sparing surgery, a very ambitious trial of 1,300 patients. And it is, by the way, the only trial listed on the website. And then there is an antigenics and industry-sponsored trial of adjuvant autologous heat shock-related peptide in 850 patients.

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To conclude, there is a paucity of high quality clinical trials, particularly in the surgical or surgical adjuvant fields. This is, however, an opportunity for creative thinking. There is a lack of trials that focus on renal cancer-specific targets. There is, for example, I only saw reported one target which looks for mutated VHL or Met, which is found in virtually every papillary cancer, or the VEGF, which is found in all clear cell carcinomas. This is surprising. This also is a very real opportunity.

So to conclude, please be creative. Our patients demand it.

Thanks very much for your attention.

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