We’re going to end this time. Thank you all for your time and expertise. [Dr Bastos], I’m going to start with you. Tell me, what are you most excited about in kidney cancer [treatments]? [It] could be a drug, it could be an approach, it could be anything.

 Well, I think as we discuss ways to improve immune checkpoint inhibitors, [it] is very important to understand mechanisms of resistance. One thing that’s very interesting for me, and that’s something that we did a few clinical trials with a drug that targets cancer cell metabolism, is for instance in this particular case, FH-deficient [cases]. They tend to have more glycolytic pano, the cancer cells tend to survive more glycolytic pano, and that shift from glycolysis to others, metabolism in cancer cells may lead to apoptosis.

 Metabolism-directed drugs seem [effective], obviously in cases like FH-deficient tumors, but they may also be extended toward the renal cells.

 I think if we take a step back from all these data, it’s kind of amazing how many folks are living beyond 5 years, right? We could not have imagined this, I think, when we started these studies. So that I’m just excited to see, and I think as we cross-compare and decide which is better, they’re all really great compared to where we were before. I am going to pick, as the thing I’m most excited for, trying to understand where the options are for de-escalation. We talked about stopping pembrolizumab, when to do it, who can be sequenced vs combination as we move toward triplets. It’s in way easier to answer that question because you just do the study and load them up up front and then compare, but really [what] you want to know is that overall survival. Can we achieve the same thing with sequence, with less, with breaks, with treatment-free survival? And it’s a hard question to answer, but I hope we can put a lens on that going forward now that we have the luxury.

De-escalation strategy, deintensification strategies. I’m doing like the two-word summary of each of your answers. [Dr Jonasch], what do you think?

 On top of tuning the immune system, I think one of the other things that’s striking, I did my board renewal and I saw that all of the other diseases have antibody-drug conjugates [ADCs] or something where we know we have CA 19-9 [cancer antigen], we have CD70. We need to figure out what is it that we want to deliver, what’s the lethal payload that’s appropriate for renal cell carcinoma? How do we take advantage of this? We now have imaging modalities, the zirconium-89, girentuximab. That tells us we can get stuff there. We need to figure out what it is we want to get there.

 I would say, I think it’s about precision medicine. I think your work, [Dr Rini], that you’re doing with biomarker development and developing signatures, how can we best identify patients for some therapies? And really looking at our trials, getting that blood that our patients gave for the studies, analyzing it and seeing what we can do with that data and really presenting that and trying to find better ways and what we can build upon. Because there are a lot of great studies that are coming out for biomarkers-selected therapy, which a lot of other tumors look at. I think if we can incorporate that, other than the IMDC [International Metastatic RCC Database Consortium] risk, that would be really important.

Thank you. These are all great answers. Really good answers.

I would say, yeah, biomarkers of course, but I might say, I think we’re about to see a wave of novel immune drugs, novel non PD-1, PD-L1 base, be it LAG-3 or TIGIT or novel CTLA-4, those novel CTLA-4 drugs. And I think we’re going to start to see those develop, see them combined in the front line, and I think we’re going to cure more patients. On that note, thanks again to our panel, this was great. And thanks to our viewing audience. Thanks for joining us. We hope you found this 

 discussion to be useful and valuable for the treatment of your patients with advanced kidney cancer.

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Shared insight on the evolving state of renal cell carcinoma management and hope for future growth in the treatment landscape.  

Renal Cell Carcinoma: Future Evolutions in Care

Let’s talk about toxicity of these regimens. They each have their toxicity, and as I mentioned, one of the reasons that maybe I don’t give more ipilimumab-nivolumab is that fear of ipilimumab toxicity. Because if you have a bad TKI [tyrosine kinase inhibitor]-based toxicity, that might be like bad diarrhea and anorexia, and you stop, and it gets better. Transaminitis, and you stop, and it generally gets better within days, maybe weeks. If you have a bad ipilimumab toxicity, that can be life-threatening. We’re all scarred by our worst experiences somewhat. I guess maybe the question, Betsy, I’ll start with you, is are you not giving more ipilimumab-nivolumab for the reasons that I may be alluding to, that I’m a little scared of that up-front toxicity and actually shortening a patient’s life instead of lengthening it?

 For sure. I think a large percentage of patients who get ipilimumab-nivolumab had to be admitted for high-dose steroids and then usually have to stop treatment. Then they’re on to just TKI alone. So that scenario is pretty common with ipilimumab and nivolumab. So it is one of the deterrents for me. Honestly, the reason I don’t turn to it more is because I truly believe the long-term data with the IO [immune-oncology]-TKI combinations is going to match that with ipilimumab-nivolumab when looked at appropriately. I don’t think, it’s not as durable and that’s colored by my clinical experience. We’ve done a lot with these drugs over the years. So toxicity and the fact that I don’t think you give up efficacy by steering away from ipilimumab and nivolumab.

Let me channel some of our colleagues now. So ipilimumab-nivolumab has a 30% tail to PFS [progression-free survival] curves.

Axitinib-pembrolizumab, presented today, was 18.4% or something.

I know we’re comparing subsets and all the caveats and statistics, and luckily there are no statisticians on the panel, but that’s going to happen. Those ipilimumab-nivolumab folks can say, “Wait a minute, it’s 30%, not 20%.”

 But the 30% is an estimate with an awful lot of censoring. Those curves are frozen in time. So the ipilimumab-nivolumab data, there’s 7-plus years of follow-up for the last patient enrolled on that study. That estimate will never change. With the axitinib and pembrolizumab, we’re seeing constant change because they’re actually continuing to collect data on these patients.

You think it’s a bit of a, I don’t want to say, methodologic issue?

 I do. I think that’s why that curve is flat, flat, flat and will be forever, because they’ve lost those patients to follow-up. You can look at the numbers at the bottom and how quickly they drop off; we can’t confirm those patients are alive and progression-free. The other thing is the survival, which is a little easier to track, those curves continue to go down. What are people dying of if they’re not progressing but they’re still dying? My guess is it is uncaptured progression. It’s a guess, but it’s filling in a gap of missing data. And related to having participated in all these studies and understanding how the data collection was different. So it’s nuanced.

I think, and maybe the larger point is, long-term follow-up of trials is super important.

We get all excited about initial results and ASCO [the American Society of Clinical Oncology meeting], plenary [sessions], and all these impact publications, which is great, but in the clinic it’s really important to know how to follow people and how long.

 We’re making decisions based on those at the front line, based on data that we anticipate for that patient in front of us 5, 10 years from now. So yes, it’s important.

How much ipilimumab-nivolumab do you use?

 I use it probably in [approximately] one-third of my patients.

 No. Because I don’t think it’s appropriate for most favorable risk patients, I don’t think it‘s appropriate. Then there‘s the intermediate poor risk groups where I think they need to have a faster response. But for us, obviously the toxicities are things that we have learned to deal with, and we still see a small percentage of individuals who have the very worrisome toxicities, like the myocarditis, the myositis, the myasthenia gravis type symptomatology. We see those, they‘re relatively rare, but even there we usually manage to get patients through those. So I‘m a little less afraid of the toxicity, but it clearly requires a team. [Those] within the department know how to take care of it. All of our subspecialists really have developed subject matter expertise. So that gives me some confidence that we can get our patients through it.

I think when the initial ipilimumab/nivolumab data was presented, I think it was a 35% high dose steroid. It was like, whoa, that’s a lot. Now, I don’t know, we’re not that afraid of high dose steroids, but we’re afraid of the sequelae of irAEs [immune-related adverse events] and needing to use infliximab and needing to use all these other things. If you put somebody on high-dose steroids and they get better, great. I don’t think that’s a problem, in general. But when they don’t get better, require the things are obviously fatal outcomes, that’s…I’m just trying to get a sense of how much that toxicity is.

 That risk exists with all the doublets because there’s IO. So it’s more with ipilimumab-nivolumab.

 But we’re always vigilant for all that.

 I think if you look at COSMIC-313 [NCT03937219]and you look at the discontinuation rates and the toxicity rates and the steroid use for the ipilimumab-nivolumab arm in that study, it is somewhat lower than it was with CheckMate 214 [NCT02231749]. I think this is all part of our learning how to use these agents over time [that’s] really has de-risked that somewhat.

I think that’s fair. We’re going to get to triplets a little bit later.

Expert perspectives on the adverse event profiles of first-line combination therapies in the advanced clear cell renal cell carcinoma space.

Brian I. Rini, MD, Cleveland Clinic

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Renal Cell Carcinoma: Future Evolutions in Care

Advanced Clear Cell RCC: AE Profile of First-Line Combination Therapies