Contemporary Management of Metastatic Renal Cell Carcinoma - Episode 3

CheckMate 214 Trial for Newly Diagnosed Metastatic RCC

Transcript: Daniel J. George, MD: We have 2 other frontline regimens that are recently approved. The CheckMate 214, with nivolumab and ipilimumab, and then JAVELIN Renal 101—which was also just presented at GU ASCO [American Society of Clinical Oncology Genitourinary Cancers Symposium]—with avelumab and axitinib. Do you want to walk us through a little of that, the data on those?

Nizar M. Tannir, MD, FACP: Yes, for the CheckMate 214, I had the opportunity to present the updated data at ASCO GU. Obviously the primary analysis was published last year in the New England Journal of Medicine. This was a fairly large, phase III trial—1096 patients, and 23% of those patients had favorable risk, 60% had poor risk, and then the rest were intermediate risk.

There were 3 coprimary endpoints for CheckMate 214. These 3 coprimary endpoints were in patients with intermediate risk and poor risk. Same stratification as all the other phase III trials they used, which are IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk factor and geography or region.

The 3 coprimary endpoints were in intermediate risk and poor risk, and OS [overall survival] and ORR [objective response rate] was significantly better in favor of nivolumab-ipilimumab compared with sunitinib. The updated data show that at 30 months’ minimum follow-up and median 32 months’ follow-up, there was a plateau, a tail, or a shoulder at the end of the curve. Twenty-eight percent of the patients with nivolumab-ipilimumab had progression-free survival.

If you look at the Kaplan-Meier curves for sunitinib, it’s coming down to the x-axis. This is what I just said earlier: it’s not fair to compare across trials, obviously because of what Bob mentioned and what you mentioned Joe about the recruitment for the trials, the different breakdown of how many patients had favorable risk versus the other. I think time will tell how these trials will stack up against one another with more follow-up. I really think what is important when we are treating patients with, say, IO/IO [immuno-oncology] therapy and a dual immune checkpoint inhibitor therapy is that you really need to look at landmark analysis for PFS [progression-free survival] and OS to really see if we are achieving a tail at the end of the curve. Because at the end, what matters to patients is achieving a CR [complete response] or a near CR, and that durability is what you really hope to achieve.

What’s interesting from the nivolumab-ipilimumab of CheckMate 214 study—which I’d like to see from the other trials with the checkpoint plus TKI [tyrosine kinase inhibitor] combinations—is can these therapies produce a treatment-free survival like nivolumab-ipilimumab does? Can patients hope to achieve a remission that’s durable? Even if it’s a PR [partial response] or near CR, can they come off therapy and be treatment-free for a long time? That has been achieved with nivolumab-ipilimumab.

I can relate the story of 3 patients of mine who I enrolled on CheckMate 214. All 3 of them had toxicity early on, which is what we see with nivolumab-ipilimumab, and they had to come off the study after they developed immune-related toxicities. One had 2 cycles, 1 had 3, 1 had 4. All 3 patients with CR are in remission—in continuous CR, unmaintained—without any further therapy after nivolumab-ipilimumab 4 years later. I think this is really what we hope to achieve with our patients. I hope to see that this can be achieved with the checkpoint and TKIs in combination.

Daniel J. George, MD: Bob, let me ask you because you’re out there in practice like many of us and the people in the audience. Help us understand. How do you balance, say, that really impressive response rate, that early hazard ratio of survival benefit of, say, pembrolizumab-axitinib, maybe a little cleaner adverse-effect profile with JAVELIN Renal 101, a little less steroid use and whatnot? The nivolumab-ipilimumab may be a little bit more toxic, but these are great results that Nizar has alluded to in terms of this really long-term, 28% progression-free survival in some of these patients who are now off therapy and with good quality of life. They sound like very different aspects to each study. How do you balance that in choosing?

Robert S. Alter, MD: Well, I think when we meet our patients, we always have to think about the multitude of other risk factors that they have, whether it’s IMDC, performance status, or individuated burden of disease, and I really have to think that every patient is individual compared with just looking at the data when we see a patient. When we talk to patients, we can educate them as much as possible. But as you said, we have to look at the data and be impressed. I think the complete remission rate of ipilimumab-nivolumab can dictate how we think. I think we believe the sequences can be quite important: how do we approach now that we have an IO TKI? What do we think when they progress as compared with having very clean IO/IO therapy? Can we easily sequence them with a TKI?

I like to look at the patients and obviously survey everything about them, look at the tumor burden, and believe there’s a need to have disease reduction. I do believe that having a TKI early can actually have a little more volume reduction compared with an IO/IO that I’ve seen in practice. A lot of our patients are not coming in with these visceral metastases that require emergent reduction of their disease. I still believe that when the data were presented at ASCO GU, the 11% complete remission rate was quite impressive. And I think we have to really believe that can dictate to a long period of time in which not only can they have a great duration of response, but we have the ability to have our patients come off therapy, and we can simply give them a vacation off their treatment, so we don’t have to believe that continuous immunotherapy, or doctor visits, or scans are the necessity for their day-to-day life.

Chung-Han Lee, MD, PhD: I would agree. I think that it’s 1 of those things in which the idea of complete response rate is very attractive. And probably even more attractive than the complete response rate is going to be the ability to come off treatment. If you have a 70% PR and a CR, functionally that’s the same unless you’re actually planning on taking them off treatment. And if we can have these long, durable periods in which they’re off treatment, this is really kind of our goal in oncology in which you give a treatment for a fixed amount of time and then you can subsequently come off. I think that for nivolumab-ipilimumab combinations, we really have been able to show that there are patients who have been able to get a finite amount of treatment and durable response. And that data still aren’t quite there yet for any of the TKI I/O combinations.

Transcript Edited for Clarity