Bladder Cancer Update & Renal Cell Cancer Update, 2017 (Video Program)Results of the Phase III ASSURE and S-TRAC trials investigating adjuvant sorafenib or sunitinib for unfavorable/high-risk RCC
7:08 minutes.
TRANSCRIPTION:
DR MOTZER: There have been a number of different trials of cytokine therapy, interferon, high-dose interleukin-2, over the years that showed no delay in relapse or prevention — of disease-free survival. And when the VEGF-targeted therapy became available, there was a lot of interest in adjuvant trials because of the robust activity that was seen with those drugs. So there’s now been about 5 or 6 of these large adjuvant trials that have been set up virtually with all the targeted drugs. And really the first one was the ASSURE trial, which was the cooperative group study in the United States, comparing sunitinib/sorafenib and placebo. And that was an 1,800-plus-patient trial. And it was kind of the grandfather of all these. And at the end of the day, there was absolutely no benefit in relapse-free survival with sorafenib or sunitinib. So more recently, the S-TRAC trial was reported. And that was an industry-sponsored study that compared sunitinib to placebo. And that trial did meet its primary endpoint showing a longer disease-free survival or relapse-free survival compared to placebo. So now we have these 2 large trials showing different results, 1 showing a benefit for sunitinib and the other showing no benefit. DR LOVE: So I’m just looking at the — right. And I see that the hazard rate in the positive trial for sunitinib was 0.76, so not overwhelming, but still, as you say, statistically significant. What were some of the explanations that have been postulated for the differences? And is this enough for you to consider or bring up the issue of actually treating people outside a trial setting with a TKI or sunitinib? DR MOTZER: Yes. There were differences in trial conduct and design. So, for example, in the ASSURE trial, patients with even Stage T1 lesions were included. T1B lesions were included in the ASSURE trial, and T2 lesions as well. The S-TRAC was strictly T3 or higher. The ASSURE trial included patients with nonclear cell histologies, and S-TRAC was only clear cell. So I think that would make a difference, because we wouldn’t really expect these drugs to benefit so much patients in the nonclear cell histology. It kind of biases the ASSURE trial against being negative. There were other differences as well. In the S-TRAC trial, there was a review by an independent radiologist for eligibility, to screen patients for metastasis. And for the ASSURE trial, it was much less screening. I believe that even a chest x-ray could be used to rule out lung metastasis. The S-TRAC trial, the primary endpoint was made by a blinded central review committee, independent. And in the ASSURE trial, it was the investigator. And there were also differences in dose as well. In the ASSURE trial, about halfway into the trial, the doses were reduced of all the drugs. For sunitinib, the full dose is 50 mg, 4 weeks on, 2 weeks off. And it was reduced down to 37.5 and to 25 as well, for dose reduction. The S-TRAC, there was an emphasis on that high dose. So all patients were treated with the 50 mg. And dose reduction to 25 mg was not allowed, just the 50 and the 37.5. So there were differences between the studies. And the primary endpoint for S-TRAC was independent review. It didn’t meet statistical significance for investigator review. The ASSURE trial was just all investigator review. So there were differences between the 2 studies regarding the patient population, how it was conducted. So the ASSURE trial was done through our US cooperative group mechanism, which is a lot of community physicians can be involved. The S-TRAC was a global trial that focused on centers of excellence worldwide. So I think that could be another factor in terms of explaining a difference. DR LOVE: A couple of things you mentioned were kind of interesting: (1), the issue of the eligibility and the lower risk in the ASSURE trial. When you look at the actual event number, was it powered adequately, the ASSURE trial? DR MOTZER: I think it was powered adequately. It was a big study, 1,800 patients. I don’t think I can criticize the statistical design. The statistics were put together by a very well-renown statistician as part of the cooperative group. But I think it was just a different population. DR LOVE: The other thing that I thought was interesting was, if I understood you correctly, you said in the — what’s it called? DR MOTZER: S-TRAC. DR LOVE: You also mentioned that the S-TRAC trial, the investigator review was not positive. Why do you think that was? DR MOTZER: It’s difficult to say. It was a secondary endpoint. It didn’t reach statistical significance, but it was very, very close. So it was trending in that direction, but it didn’t quite reach statistical significance. For the ASSURE trial, there was absolutely no benefit. It was a hazard ratio of, like, 1, so that there was absolutely not even a trend in favoring one of these drugs over placebo. DR LOVE: Now, you actually put patients on the S-TRAC trial. What was it like getting people through a year of adjuvant sunitinib? DR MOTZER: Yes. I was the highest enroller worldwide in that trial. I think I accrued about 25 patients. And so I didn’t find it so difficult. I participated in that trial, as well as the PROTECT trial. But patients coming to my center tend to be very motivated to come to Memorial Sloan Kettering. They tend to come from distances, focused on clinical trials. And also, Neil, I have had a lot of experience with sunitinib and managing toxicity. So I think that that experience as well, probably, it can be a factor. |