NCCN Guidelines and Treatment Selection in Non–Clear Cell RCC

Drs. Laurence Albiges and Martin Voss review NCCN treatment recommendations for metastatic non-clear cell renal cell carcinoma (RCC), highlighting differences in management across papillary, FH-deficient, and chromophobe subtypes. They examine evidence supporting cabozantinib, lenvatinib plus pembrolizumab, and cabozantinib plus nivolumab in papillary RCC, including findings from PAPMET and the evolving role of immunotherapy combinations. The conversation also explores treatment options for aggressive FH-deficient tumors, including erlotinib plus bevacizumab, and the challenges of treating chromophobe RCC, where responses to immune checkpoint inhibitors are less consistent. They emphasize the importance of accurate pathologic classification and further prospective trials to guide subtype-specific treatment decisions.

Transcript:

Dr. Albiges:  Hello, my name is Laurence Albiges. I’m a medical oncologist working in France at Gustave Roussy, and both my clinical and research focus are patients with kidney cancer. Welcome to OncoNexus. It’s my pleasure to be here with Dr. Martin Voss.

Dr. Voss: Hello. It’s good to join you, and thank you for joining us for this session today. I’m Martin Voss. I’m also a GU medical oncologist. I practice at Memorial Sloan Kettering Cancer Center in New York, where my focus is also renal cell carcinoma.

Dr. Albiges:  And so for today, we’ll be discussing non-clear cell treatment management. So maybe Martin, can you explain to us how the NCCN guidelines strategy ranking works?

Dr. Voss: Yes. So the NCCN, the National Comprehensive Cancer Network, puts out expert guidance to practicing oncologists in the United States, and it is very helpful, particularly in scenarios that are less common. So non-clear cell kidney cancer ranks high in that regard.

It’s a panel of experts, typically about 30 experts, that have a disease focus in renal cell carcinoma, and the NCCN has expert groups that provide guidance on any oncologic entity. But for the kidney cancer group of experts specifically, it’s about 30 folks, and it is chaired by my colleague Robert Motzer. He’s the chair, and Eric Jonasch for a long time has been the co-chair.

So they lead that group, and they meet regularly and review emerging data from clinical trials to provide evidence-guided recommendations to practicing oncologists. There is a dedicated set of guidelines and algorithms for clear cell kidney cancer, and then there’s one that we’re talking about today, which is non-clear cell renal cell carcinoma.

The guidance that the expert panel gives is, as I said, founded on published data, and they do try to tier their recommendations based on the level of evidence there is. So they typically have a preferred recommendation, but they also list other options where evidence exists that is supportive of certain strategies.

So let’s talk about non-clear cell kidney cancer. In the first line, untreated metastatic non-clear cell kidney cancer, the preferred options that are listed in the NCCN compendium include single-agent cabozantinib, and the reason that is still listed is because of the PAPMET study randomized trial.

So this is one of the few randomized data sets in this space that compared different kinase inhibitors. It was published in The Lancet several years ago and looked at cabozantinib versus sunitinib versus two other kinase inhibitors, and ultimately showed that cabozantinib came out superior in terms of progression-free survival and objective response. Many at the time then considered that the standard TKI, certainly for papillary renal cell cancer, and I think that extended toward other non-clear cell subtypes.

Subsequent to those data, which are still anchored in the NCCN as an option, are non-randomized data that justified the use of two combinations: lenvatinib plus pembrolizumab, based on the Phase 2 KEYNOTE-B61 data that you and I were both very involved in, and then cabozantinib plus nivolumab, based on a Phase 2 study that was conducted at our own institution.

So the NCCN supports these strategies and lists several other strategies also. Ipilimumab plus nivolumab, there are now randomized data from our European colleagues. I know that you were involved in that effort based on the SUNNIFORECAST data that looked at ipilimumab plus nivolumab compared to dealers choice, right older standards and also showed evidence.

So what you see in the NCCN guidance’s, it points practicing oncologists towards where the data is. For non clear cell kidney cancer the data is more limited, there is less randomized data. Nonetheless, these are what experts consider the data sources of greatest validity one we try to make decisions for our patients.

Dr. Albiges:  Yeah, so maybe one comment around non-clear cell. It’s obviously a mixed bag of different tumor subtypes, so we have to raise awareness that these are not a single entity but different entities. Some of those trials have been developed specifically for one subtype, such as papillary, because that’s the most common subtype, and we are able to have dedicated trials, including some randomized data, as you highlighted with PAPMET.

But on the other hand, there are also pooled trials where we have the different subtypes. So maybe one quick word. We know that non-clear cell has a worse prognosis than clear cell. We also know that sometimes it’s not easy, and so pathologists have to make the decision based on their pathology review. Is that a high-grade papillary tumor? Could it be an FH-altered tumor? The other most common entity is chromophobe, and we can speak to that entity afterward.

In the past, papillary included not only FH-altered tumors but also TFE3 translocation renal cell carcinoma, which tends to occur in younger adults. And then we have even rarer entities such as RMC, renal medullary carcinoma, for instance. Are there any other subtypes you would like to highlight? Because maybe we’re going to speak to the different subtypes themselves.

Dr. Voss: I think those are the important ones, and I think what is of interest to the audience is that these are moving targets. We see with updated pathology guidelines and categorization, the latest WHO classification, for instance, that some of these are now broken down into other subsets, and some of these are being redefined and given new names.

And that can be tricky because the clinical trial data sets that we look at take years to conduct, analyze, publish, and make it into clinical practice. By the time we go from designing a trial to publishing and implementing the data, some of these categories change. I think you listed all the important ones. Right back to your question, I do think for the smaller entities, there are a few that oncologists must be aware of because they perform so differently.

Some of them are not recognized specifically with great detail in the NCCN guidelines. I think one that you pointed out is renal medullary carcinoma, which is difficult to treat. Collecting duct carcinoma should be added to the list. Collecting duct carcinomas, right? So these are chemotherapy-sensitive entities that we don’t tend to treat with the same treatment paradigms.

But I want to talk a little bit with you about FH deficiency because that is one of the entities that really has been newly defined, redefined, and differently defined from before. So I’m curious how you think about this and where they fit into these paradigms that we talk about. What data do you tend to look at for FH-deficient kidney cancers?

Dr. Albiges:  Sure. So just having in mind that FH deficiency, we used to say in the past HLRCC, is within a syndromic presentation, usually young adults, including females, so a male and female balance for this subtype, and hereditary syndrome. These tumors are usually extremely aggressive and tend to have high-grade papillary-like pathological features.

Notably, they have a metastatic burden that is a bit different from what we see in clear cell, with more peritoneal disease. And so those patients usually, from my clinical experience, require systemic therapy because of rapidly growing disease and symptomatic ascites and so on.

So there are two options that I would consider. One of them is IO-TKI, so VEGF-TKI plus immune checkpoint inhibitor, with two newly listed possibilities: lenvatinib plus pembrolizumab and cabozantinib plus nivolumab. Recently, we had the cabozantinib-nivolumab data reported in this subtype, and these are interesting data.

The specificity of this subtype is that there have also been data generated prospectively looking at the combination of erlotinib plus bevacizumab, so EGFR plus VEGF inhibition. And here, the data set was a very clean data set of patients with FH-altered tumors, showing a good disease control rate and a long progression-free survival. So to me, these are the two options: IO-TKI or erlotinib plus bevacizumab.

Dr. Voss: And erlotinib plus bevacizumab is recognized in the NCCN guidelines, just to go back to our framework here. It does point to certain circumstances where unique strategies can be considered. So if you look at the NCCN guidelines, you will find a reference to the New England Journal of Medicine paper from the NCI group and the data specifically there.

Excellent. Yeah, so I think the opposite of that on the spectrum is probably papillary kidney cancer, which is by far the largest subgroup here. And there we have lots of data to guide our practice. And like I said before, single-agent TKI is still listed as an option in the NCCN. TKI therapies are listed. Do you want to speak a little bit about the papillary experience?

Dr. Albiges:  Yeah, I think you highlighted the fact that it was built on the PAPMET study, and kudos to the investigators who started randomizing patients with papillary RCC, the most common form of non-clear cell. And they identified cabozantinib to be superior to sunitinib prospectively.

Interestingly, in the study, two other arms were tested with MET-focused strategies, namely savolitinib and crizotinib, but those two arms were dropped because of futility. And the reason for that is that we knew that a subset of about a third of papillary tumors seemed to have what we call MET pathway alterations. And that comes from earlier times when we previously had type 1 and type 2 subtyping of papillary, which has now been dropped.

Yeah. But it was low-grade and high-grade, basically. And so the former type 1, low-grade papillary, tended to have those MET alterations, and that had triggered the idea of targeting MET. There have been subsequent studies looking at MET inhibitors in a biomarker-selected population. That’s the SAVOIR strategy and then subsequently SAMETA.

So to me, the data we have as of now support either single-agent cabozantinib, as in the guidelines, or an IO-TKI. And you listed the two non-randomized but large Phase 2 studies, so KEYNOTE-B61 with lenvatinib-pembrolizumab or the cabozantinib-nivolumab data that have been generated by your institution. And what is very important to me here is the response rate and PFS that were very similar in the two trials, achieving a 50% response rate in the papillary subtype.

So this is great because if you think about single-agent TKI, usually we are somewhere between 20% and 30%. So 50% when you have an IO-TKI strategy such as lenvatinib-pembrolizumab or cabozantinib-nivolumab, and long PFS, with an extended PFS for KEYNOTE-B61 of 17 months. So this is much longer than what we had with single-agent TKI.

Dr. Voss: Yeah. And it goes back to what you said before. This is not quite as good as what we’re used to seeing with clear cell kidney cancer, right? You made that point before that non-clear cell cancers have outcomes that are a little bit worse.

But I think of papillary specifically as a disease entity where I can apply very similar treatment paradigms to those used for clear cell kidney cancer. They do respond very reliably, 50%, right? Lenvatinib-pembrolizumab in clear cell is even higher, 70%, but we do see complete remissions in papillary, which is very important when thinking about that.

So there were CRs on both TKI-IO trials. The duration of response is not quite as good as it was in the clear cell trials, but it is certainly better than historical controls for a TKI. So I think the combination of a TKI and IO makes sense.

And like you, I feel that the fact that these two studies showed such similar signals with similar strategies, again reflecting what we experience in clear cell kidney cancer, gives a lot of strength to that strategy.

Dr. Albiges:  And so at the ESMO meeting, we’re having PAPMET 2 being presented. Yeah. I think there are lessons to learn from this. It’s a great academic effort again.

It questioned the role of adding IO on top of TKI, but also showed that now, routinely in practice, those patients may not be randomized because there are believers that we have already demonstrated that IO-TKI is the go-to strategy. What is your take on PAPMET 2?

Dr. Voss: It’s a challenge, certainly. I mean, kudos to the investigators for being so rigorous about their approach to this and saying, “Well, randomization is the gold standard. We should prove that point.”

But I find it very hard to ignore the very robust efficacy signal that we’ve seen in two decent-sized Phase 2 studies. And I think the experience has also been that we had all been treating patients with clear cell regimens outside of trials for a while, and certainly my sense has been that these patients truly can benefit and achieve durable responses.

Dr. Albiges:  And maybe now to wrap up, another subtype for which you’ve been leading the effort is chromophobe RCC, metastatic chromophobe RCC. So what is in the guidelines? What is your recommendation?

Dr. Voss: So the NCCN guidelines do not specifically speak to the chromophobe subtype. They just speak to non-clear cell kidney cancer, and there’s no annotation specifically about what to consider. However, I do think they are unique in that we know a couple of things that set them apart.

For one, the disease dynamics typically are less aggressive than they are for some other non-clear cell kidney cancers. If you took all the papillary and all the chromophobe cancers and just looked at the natural history of disease, the chromophobes probably would be a little bit less aggressive. Number two, they tend to respond quite well to kinase inhibitor therapy. We’ve known that for years, and they do so in these combination trials also.

And number three, if we go through the series of Phase 2 studies that have been conducted in non-clear cell kidney cancer through the years that integrate checkpoint inhibitors, either checkpoint inhibitor monotherapy, CTLA-4 and PD-1 combinations, or PD-1 and TKI combinations, there is a real step-down in efficacy when you go from some of the other non-clear cell subtypes to the chromophobes.

And the sense really has been recurrently that there are certainly patients with chromophobe RCC who can benefit from PD-1-based therapy, but the proportion of those is markedly lower. And consistently throughout all of these trials, we do not see CRs in that setting.

So there’s something different about the immune biology and responsiveness to immune checkpoint inhibitor therapy in chromophobe RCC. I myself have moved away from saying that they should not get checkpoint inhibitors. I think there are plenty of chromophobe patients who can benefit, but my expectations aren’t quite as high.

And I do think it says a lot about where we need to go in the future in drug development. I do think they need a specific strategy. I do think the surfaceome is very important for chromophobe, and thinking about unique targets in that disease that may help us apply some of these newer strategies, T-cell engagers, radioligands, right?

Maybe non-checkpoint inhibitor approaches are the way to go, and thinking about them as their own entity.

Dr. Albiges:  Great. So hopefully more data to come, and I hope prospective data within each of these different subtypes. Well, thank you very much, Martin.

Dr. Voss: Thanks. Nice talking to you as always.