Daniel George, MD: I want to turn our attention to the control arms in these studies, because everybody is comparing to sunitinib, and in particular, sunitinib 4 weeks on, 2 weeks off. Now, there have been comparisons to sunitinib 4 weeks on, 2 weeks off with pazopanib, and we’ve seen a very different side effect profile. Walt, do you have thoughts on that study, the COMPARZ study, and how do you interpret that now in the context of these ongoing studies?
Walter Stadler, MD: Well, I think that the control arm of sunitinib at the FDA-approved schedule gives the companies the greatest potential for winning in the I-O combinations, in essence because the 4/2 combination is difficult to tolerate and has real problems. Most of us, and most practitioners in the community, will rapidly switch to alternative schedules, and there’re data to support that, or use an alternative TKI such as pazopanib, and that is not part of these particular trials. Therefore, I have some concerns that the dose intensity in the control arm is ideal in these particular trials. Once again, leads back to my contention that survival really has to be observed in order though. We don’t have any randomized phase III trials to compare 4/2 versus 2/1. We had one study published in Annals of Oncology that showed 2/1 is really better tolerated, it has better efficacy. But we recently had a paper published about the 2/1 schedule where the primary endpoint was grade 3 events and was not different between both arms.
Daniel George, MD: I guess I was less worried about that regimen and the data we do have, which is the COMPARZ study you were part of. There we have a clear difference in safety signal, no difference in efficacy between sunitinib and pazopanib. How will you compare that safety signal now to the signals we’re going to get from these trials?
Toni Choueiri, MD: I would not say safety. I would say tolerability, because the treatment discontinuation for side effects from pazopanib and sunitinib, and the death on trial from these drugs, were not different. But from tolerability, that’s an issue, and people have used all kinds of sunitinib schedules. I do agree that pazopanib, in general, not overall, is better tolerated—and that’s going to be an issue. We may revert back to what Walt said initially, overall survival, which is going to be a problem, because patients on sunitinib are going to crossover, and get standard of care, checkpoint to blockers.
Daniel George, MD: That’s right and, in particular, the good risk. Because most of these studies that are being done now with I-O plus VEGF are being done in all-comers, not necessarily in the intermediate/poor-risk patients.
Toni Choueiri, MD: Correct.
Daniel George, MD: How are you going to look at the good-risk patients within that study and begin to see an overall survival benefit there? Or is it skewed by the other group?
Richard W. Joseph, MD: Yes, it’s going to be very hard to interpret that data. Everybody is very excited about axitinib, and pembrolizumab having a response rate of somewhere in the 60s or so. But if you look at for instance, sunitinib and the CheckMate-214 in the favorable-risk patients, there was over 55% right there. So, you’re wondering how much of this is the combination versus if you sequence these. I’m not totally convinced VEGF plus I-O is going to be better overall. Maybe for some, but not necessarily for all, and hopefully I think we’ll have some better biomarkers to help guide us. Like who’s going to be VEGF by themselves? Who’s going to be both? Who’s going to be just I-O? That will hopefully be the future of kidney cancer.
Robert J. Amato, DO: You brought up the word sequential, and I wasn’t sure where you were going to go with it.
Daniel George, MD: That’s our next section.
Robert J. Amato, DO: But the challenge around this table, in my opinion, is, everything’s combining 2 drugs. You pick your 2 drugs based on whoever’s in that back room that wants you to do the study. Well, why aren’t we looking at these drugs sequentially? What should come first? Which TKI drug augments the immune system to make an I-O ripe to work when you sequentially study that?
Daniel George, MD: I think that’s a great question, Bob, and that’s why we’re looking at the OS here, independent of the progression-free survival. Because that first progression might look significant, but that second progression, to your point, the sequential treatment might even out. But if we see an overall survival signal, then presumably that second progression—which is just hard to measure in studies, would also have been beneficial. So, that I think is the strategy, and we need to be careful when we interpret these studies going forward on just how much of a clinical benefit are we really seeing.
Robert J. Amato, DO: The other point that was brought up: the inflammatory issues around both agents, both fields. If you do it sequentially, well you’re going to know which of the drugs are creating the more likely inflammatory component. Whether it’s the colitis, whether it’s the hepatitis, you’ll know and you’ll have a better feel.
Daniel George, MD: That’s a great way of phrasing it, too, because I think that’s right. When we can de-compartmentalize the toxicities, we know how to manage it, we’ve done that. This is going to be new, trying to manage toxicities that might be related to both agents, and that’s something we’re going to have to look for in the future.
Robert J. Amato, DO: When in error, I’m a big cisplatin fan. I grew up studying testis cancer, that’s our drug in bladder cancer; so, you knew what you were dealing with. Here these drugs don’t go away. They have to stay on them chronically. So, what are the chronic toxicities a year later from being on a checkpoint inhibitor or being on a combination of these drugs? Economically, the pocketbook for these drugs is steep. You can’t stop these agents without potentially seeing exponential progression or progression. So, how do we educate not only ourselves but those that are out there?
Daniel George, MD: More questions than answers is how I would summarize this section.
Transcript Edited for Clarity