NCCN Guidelines Update: Impact of Ipilimumab and Nivolumab as Preferred Regimen for ccRCC

David Braun, MD, PhD, of the Yale School of Medicine, shares insights on the recent updates to the NCCN guidelines, focusing on the inclusion of ipilimumab and nivolumab as a preferred regimen for favorable-risk clear cell renal cell carcinoma (ccRCC). Dr. Braun provides an analysis of the long-term data from the CheckMate 214 trial, highlighting how this shift in treatment protocols could influence clinical practices. He also explores the broader implications of these changes, including advancements in diagnostic tools, personalized treatment planning, and the evolving role of combination immunotherapy in the management of ccRCC.

0:25: IMDC risk stratification and its prognostic use.

1:00: Early data from CheckMate 214 and sunitinib vs ipilimumab/nivolumab for favorable risk patients.

3:25: Long-term data from CheckMate 214 changing the perspective.

6:04: Upgrading the level of evidence for adjuvant pembrolizumab.

9:14: Challenges in diagnostic tools for kidney cancer. 

12:32: Advancements in combination immunotherapy.

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What are your initial thoughts on the recent update to the NCCN guidelines, specifically regarding the inclusion of ipilimumab and nivolumab as a preferred regimen for favorable risk ccRCC? How do you believe this will impact treatment protocols?

Dr. Braun: It’s a really important question. I think when the IMDC risk stratification criteria came out, the goal, the design of it was to be prognostic, was to say, okay, on average, how are patients with favorable risk disease or intermediate risk or poor risk disease, how are they likely to do over the coming months to years? And while it was designed in the era of anti-angiogenic TKIs, we know that in the current immune therapy era, it is still very prognostic. But I don’t think it was ever really designed to be a predictive tool to say, this person should get drug one or drug two. But that’s exactly how this ended up being used for CheckMate 214, where initially the early data really suggested a benefit for ipilimumab and nivolumab over sunitinib in that group of patients that had intermediate and poor risk disease. And that’s where the FDA approval came, and that’s where the NCCN guidelines really focused.

And the favorable risk patients, the patients with favorable risk disease, those are patients where in the early parts of the trial, nivo plus ipi, nivolumab plus ipilimumab really did not seem to have a huge amount of benefit. If anything, sunitinib seemed to do a bit better. Those patients treated with sunitinib seem to have a better progression-free survival, better response rates than those treated with immunotherapy. I think what’s really changed has been the long-term data and as long-term data has emerged that we have not just two years of follow-up or three years or four years, but five, six, seven, eight years of follow-up for the CheckMate 214 trial. I think what we’ve seen is those curves cross for the favorable risk patient. Where yes, maybe those early days sunitinib is slightly favored, but over the long term, the durability of nivolumab plus ipilimumab comes through even in that favorable risk group.

And so I think that’s a long way of saying I think this is a really welcome change to the NCCN guidelines. I think it’s saying that the IMDC criteria are important but are not a predictive tool, so shouldn’t necessarily direct therapy based on IMDC risk stratification, which I think is probably correct. And I think it acknowledges that in the long-term, patients with favorable risk disease who get immunotherapy still do really, really well with nivo plus ipi. And so when you combine all these factors together, I think this is important and welcome change. And I think it’ll lead to more ready adoption of ipilimumab plus nivolumab as a good choice for all patients with clear cell renal cell carcinoma, not just those with intermediate or poor risk disease.

In your opinion, what evidence or clinical data were most compelling in supporting the addition of ipilimumab and nivolumab for favorable risk ccRCC? Can you elaborate on the key studies and their outcomes that influenced this decision?

Dr. Braun: This is really the long-term outcomes from the CheckMate 214 trial. The CheckMate 214 trial was the pivotal trial that brought immunotherapy to the frontline setting for advanced clear cell kidney cancer. It was a trial of the combination of ipilimumab and nivolumab versus the comparator arm of sunitinib, a tyrosine kinase inhibitor. And so while this trial was overall positive, which is wonderful, improved the response, progression-free survival, overall survival really was a very meaningful landmark trial. The benefit seemed to really come in the early days for those patients with intermediate and porous disease by IMDC classification. And so when the FDA approval initially came, it really came for those patients with intermediate and porous disease.

But what’s changed is the investigators on the CheckMate 214 trial have done really an outstanding job of continuing to update the clinical data year after year. And this is why long-term follow-up is so important for these large clinical trials. And so now that there’s really extended follow-up, we can go back and the original publication of the 214 trial was in 2018, and here we are in 2024, still getting updates six years later. And so the most recent update was presented by Dr. Nizar Tannir from MD Anderson. It was presented at GU ASCO Symposium earlier this year in 2024, and it represented really the long-term outcomes, eight-year plus outcomes for patients with advanced kidney cancer treated as part of that CheckMate 214 trial.

And there are many, I think, important aspects to that update that applies to all patients with clear cell kidney cancer, really seeing the durability of response for those patients for whom ipi and nivo was a successful treatment. But what was really helpful to see was that favorable risk population that while initially sunitinib appeared to have some slight benefit over ipilimumab in terms of progression-free survival, that as time went on, those curves actually crossed. And so in the long term, as you go to four, five, six, seven years out, those patients treated with nivo and ipi, some of those patients really have durable survival. And that’s really, I think the main thrust of evidence that led the NCCN to decide that this is really a preferred regimen even for the population of patients with favorable risk disease.

What other significant changes or updates in the NCCN guidelines do you find most impactful for the treatment of ccRCC? How do you think these changes will alter current clinical practices?

Dr. Braun: I think one of the main ones is probably sort of upgrading the level of evidence for adjuvant pembrolizumab. I think that’s probably one of the most notable changes for this round of NCCN guidelines. I think it obviously was an option before it had an FDA approval, and that was based on a benefit in terms of disease-free survival compared to placebo in the adjuvant setting. But what’s really changed is the presentation subsequent publication of the overall survival data. And this is really, really important because it is really the first adjuvant trial in kidney cancer to be successful. So the first one to show not just disease-free survival benefit, but true overall survival benefit and frankly, for across disease types for an anti-PD-1 immune checkpoint inhibitor, there’s not a lot that shows a true overall survival benefit in that adjuvant setting. And so this was a really important, again, update of an existing trial.

The KEYNOTE-564 trial had been presented and published recently, but the updated results provided mature overall survival data that allowed NCCN panel to really upgrade their level of evidence to support this. And I think this will change practice, I think for oncologists and patients alike, I think it’s one thing to say the disease-free survival might be improved with a therapy, there might be in effect a delay of the disease coming back. But that’s different from saying it might actually prevent the disease from coming back by improving overall survival. And I think that’s what we’re starting to see here now as well. I think there’s a lot of very, very reasonable questions that have arisen about magnitude of benefit. It’s important, but there’s still work to go to improve many more patients’ lives with kidney cancer in that adjuvant setting.

And there’s open questions I think about what are subsequent types of therapy that people have gotten. And I think those are all reasonable questions that we can dive into. But I think at a 30,000-foot view, this is a positive adjuvant trial that’s successful in not just improving disease-free survival, but also overall survival. And I think the NCCN panel was absolutely right to sort of upgrade that level of evidence.

What advancements or innovations in diagnostic tools and techniques are highlighted in the updated guidelines, and how do you foresee these improving early detection and personalized treatment planning for ccRCC patients?

Dr. Braun: I think there’s a lot of excitement going into the development of new diagnostic tools, biomarker development. I think a lot of that’s not going to be in NCCN for a lot of years. And so I think what’s going to find its way into the NCCN toolkit is going to be relatively limited, but my hope is in the coming years, we’re going to see more and more tools for things like early detection and personalized treatment. So on the early detection front, there’s been a lot of work across many types of cancer for thinking about non-invasive tests to identify, diagnose, detect the presence of a cancer, things like cell-free DNA.

This has been really challenging for kidney cancer. Kidney cancer compared to other tumor types doesn’t shed a lot of its DNA into the bloodstream. So it’s actually very hard to detect. There’s a study done now a number of years ago where they looked at cell-free DNA from over 20,000 samples across different types of tumors and looked how much DNA could they actually find shed by the tumor. And whereas things like colorectal cancer and other tumor types were on one end, all the way on the other end in terms of being really low amounts of shed DNA were things like kidney cancer and actually glioblastoma, the brain tumor.

Of the tumor type *actually kidney cancer at the lowest amount of DNA in the blood of any extracranial tumor. So it really is a challenge. But there is, I think, reason for optimism. I think there’s newer approaches that look at not just DNA, but modifications to DNA, the so-called epigenome, whether that’s methylation or histone modifications, both of which now can be actually measured within the blood. Those provide, I think, new tools that might help us tease apart is there kidney cancer present or not? Is there any left after surgery? Sort of key questions that a non-invasive blood test would be really important for. And I think we’re going to see big developments hopefully in the years to come in those spaces.

For personalized treatment planning. I think it’s an ongoing challenge. The idea is to have a biomarker that would help us select, for instance, whether a patient would be best benefited by drug one or drug regimen two, whether a patient is likely or not to get side effects. These are questions that are really important in the clinic that we don’t have good biomarkers for. And then there’s a huge amount of excitement looking at now different domains, whether that’s the tumor microenvironment, whether that’s tumor genetics, whether that’s the transcriptome of gene expression, either of a whole tumor or individual cells. There’s looking at the architecture of cells within a tumor, so-called spatial approaches. All of these are exciting, but none of those are primetime ready for the clinic yet.

I think frankly, the closest we come to personalized treatment planning is fairly old-fashioned, but important, which is the presence of sarcomatoid features, sarcomatoid differentiation within a tumor. That’s something that’s purely made morphologically by looking at the tumor and actually seeing that sarcomatoid portion. And why that’s important is I think now that we have abundant evidence to say those are patients that absolutely should receive an immune checkpoint inhibitor, those are patients that do substantially better when treated with immune checkpoint inhibition compared to not receiving immune checkpoint inhibition.

So out of all of the fancy diagnostic tools we have, that’s still presence of sarcomatoid features is the one that’s truly ready for the clinic today. But again, I hope that in the coming few years we’ll see some of these other modalities from transcriptomics, genomics, spatial tools, the microenvironment, all of those begin to integrate together and have better predictive tools as well.

Looking ahead, how do you envision the role of combination immunotherapy evolving in the treatment landscape of ccRCC?

Dr. Braun: I think combination immunotherapy will be absolutely critical. I think the questions that will be important is what are the rights combinations? What are the drugs to use in combination? And what is the type of benefit that you’re getting? And the reason why I think that’s critical to define is we know that if you add more drugs together, there’s going to be more side effects. Each drug has its own side effect, and if you have two of them, that’s going to be more than one. If you have four of them, that’s going to be more than two. And so you really have to define what is the goal of what you’re trying to do by combining multiple drugs together.

And in my mind, the overriding goal really should be to try to eradicate disease. I think this is something that people often shy away from, particularly in advanced or metastatic setting, but if you ask patients, and people have done this, [inaudible 00:13:35] has done this survey among patients that really, that is the goal. Complete remissions and durable remissions, essentially eradication of disease. And I think with immunotherapy, it’s provided a proof of concept that even in that metastatic setting, such eradication of disease is possible, it’s just not frequent enough. It’s still a far minority of patients for whom those current immune checkpoint inhibitors work really well, well enough to really hopefully get rid of the disease.

And so when you think about adding more drugs, I think that is a worthwhile endeavor. I think it should be done in ideally a rational way of thinking, why does a pairing of certain drugs make sense together? I think that’s important. Not just randomly throwing drugs together, though there obviously is benefit to empiricism as well, but as much as you can do this rationally, I think there’s a benefit. But also thinking what is the goal of what you’re trying to achieve? If you have four drugs together and it increases progression-free survival by three months, that might be a positive end point, but if it’s not actually curing more patients and it’s giving a lot more toxicity, is that really a meaningful benefit?

And so I think, thinking through really what is the benefit you’re going to get. I have a very memorable patient of mine who anytime we would start a new treatment, he’d ask very plainly, much more eloquently than I ever could, “Is the juice worth the squeeze?” And I think that’s really the question for these combination regimens. You’re going to have more side effects, probably you’re going to have better short-term outcomes like response and these sorts of things. But is the juice worth the squeeze? Is the combination of these drugs going to improve the tail of the curve leading to actually eradication of disease for more patients? I think that’s what’s going to be critical.