Panelists: Robert A. Figlin, MD, Cedars-Sinai Medical Center; Thai H. Ho, MD, PhD, Mayo Clinic Arizona; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Michael B. Atkins, MD, Georgetown Lombardi Comprehensive Cancer Center; Sandy Srinivas, MD, Stanford University Medical Center
Robert A. Figlin, MD: Let’s turn our attention to some evolving data. In kidney cancer, we spend a lot of time looking at advanced disease. We have targeted and developed many drugs, over the past decade, in metastatic disease. And for the first time, Michael, we’re starting to see some evolving data that suggest that, in high-risk resected disease before a patient has metastatic disease, there might be some benefit for some of the therapies that we’ve used over the past decade.
It’s a bit confusing because it’s conflicting. We have data from ASSURE, we have data from what’s called S-TRAC—which I’ll ask you to describe—and, most recently, data from PROTECT. Where is the field, as you understand it, with respect to high-risk resected kidney cancer in the absence of metastatic disease?
Michael B. Atkins, MD: I agree it’s confusing. There was great excitement when the VEGF inhibitors were first tested in kidney cancer in patients with metastatic disease. We saw significant prolongations in progression-free survival. Then, overall, the survival appeared to be prolonged over what it was when we were using cytokines. And so, there was a push to try to move those therapies quickly into the adjuvant setting to see whether we might have a similar impact.
There was always a question about whether using a treatment that delayed progression-free survival but didn’t produce durable responses, except in the rare patient, was really going to be able to have an impact in the adjuvant setting. The hope had to be that when you were treating patients who had smaller tumor burdens and less heterogeneity in their tumor, by giving an active drug that targeted blood vessels rather than the tumor, you could somehow get rid of the last tumor cell and produce some cures.
We used to debate all the time whether that was possible or not. We all hope that at least there would be a delay in relapse-free survival. And in the ASSURE trial—the first one that reported out—which randomly assigned patients to either sorafenib, sunitinib, or placebo/sunitinib or sorafenib, there was a comparison of both of the active treatments with the placebo group without comparing the active treatments with each other. There was really no benefit in terms of either relapse-free survival or overall survival in a study that involved 1800 patients for either sunitinib or sorafenib. The treatment was given for a year, and the time to relapse was somewhere around 5 or 6 years, median. And so, it’s possible that there might have been some early subtle benefit that was lost when you stopped the treatment. In that study, a lot of patients didn’t tolerate receiving these drugs in the adjuvant setting. There was some toxicity, so many patients stopped before they got their third year of therapy. There were a lot of explanations that were put forward, but the overall feeling was it was not a home run.
The S-TRAC trial—which looked at sunitinib compared with placebo in a higher-risk population and was, therefore, a smaller study to get the same number of events—did show a small benefit of a few months in terms of relapse-free survival, but no benefit in terms of overall survival. The question is, is that really worth the toxicity of taking that therapy?
The PROTECT trial was probably closer to the ASSURE trial, showing not much benefit for the attempt-to-treat population for pazopanib, compared with placebo. We went back and looked at the ASSURE trial and tried to identify the type of patients who were on there, who would have been eligible for the S-TRAC trial in the ASSURE trial, and tried to reanalyze the data to see whether or not we could turn it into a positive trial by focusing on a different subset of patients who then were in the trial as a whole. And, no matter how we analyzed and we tried to narrow it down, there was still no benefit for sunitinib, compared with placebo. My sense is there may be some delay in relapse-free survival that happens with these treatments, but the majority of patients are not having their disease go completely away. When you stop the treatment, the tumors tend to catch up, and there ultimately will be no difference in overall survival.