Cytoreductive Nephrectomy and RCC Biomarkers: What’s Next in Kidney Cancer Treatment?

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a panel of experts discussed the latest research, emerging therapies, and best practices for treating renal cell carcinoma (RCC). Moderator Dr. Katy Beckermann of Tennessee Oncology was joined by Drs. David Braun, Matt Campbell, Brad McGregor, and Katie S. Murray in the discussion.

In part four, the panelists examine how cytoreductive nephrectomy fits into RCC treatment while assessing the growing influence of biomarkers on decision-making. The discussion covers the best timing for surgery, the effects of systemic therapy, and new approaches aimed at enhancing patient outcomes. Finally, the panel highlights advancements in imaging techniques and ongoing research into bone metastases for improved disease evaluation.

View the next segment on Navigating Refractory RCC: Sequencing, Combinations, and Emerging Therapies.

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Dr. Beckermann: To dive in a little bit on some of the nuances in frontline treatment. So Katie, I am curious as far as a delayed cytoreductive nephrectomy practice. I know we went through the TKI era of saying there is no benefit to upfront nephrectomy. But what is your current practice? Are you doing upfront? Are you doing delayed? If you are doing delayed, what timeframe?

Dr. Murray: I think the answer is all across the board, right? It is hard to say this is what we always do. I do think there are select patients with maybe lung-only disease that is very small, that Matt kind of described, where that patient is going to go on for a nephrectomy. If you think of that as the cytoreductive concept from that situation. But I do think this delayed cytoreductive is huge right now. And you guys have just said the word “cure” like five times in the last however amount of time. And that is a cure. And then we are still dealing, potentially, with this primary tumor. So if we start talking this word “cure” and you are getting it with IO-IO or triplet or whatever that is, where does that timeframe come in for that delayed nephrectomy? Right? So I did not answer your question from a timeframe perspective, but I do think, to show that the disease is not that progressive and the patient has good tolerability and you can do a period of time of stop, I do not think doing a delayed cytoreductive nephrectomy is a bad idea. I think it is a good idea.

Dr. Beckermann: Yeah.

Dr. Murray: I do not know if your practices and your urologists are kind of leaning the same way. I think one of the other concerns is what is it going to be like operating on these people after IO therapies? We have some experience in other disease states at the same time, and I have heard mixed things, but I think it is fairly straightforward from a surgical standpoint.

Dr. Beckermann: And do you find, I was going to ask, I know sometimes we do a delayed cytoreductive nephrectomy and we are having a great response systemically, but maybe the primary kidney tumor is the thing causing the problem. So what percentage of time do you think you are doing a delayed cytoreductive nephrectomy because that is the primary site of progression? It is kind of an oligoprogressive disease versus they are in a near CR and we just want to get the kidney out.

Dr. Murray: Yeah. So maybe a quarter of the time or so. I do not know. I mean, I am just guessing that out of the air. But I definitely think we see those patients. Those are the ones that you guys are seeing, and you call us up and send us back and say, “Hey, it might be the time.”

Dr. Beckermann: Yeah.

Dr. Campbell: Yeah. It is pretty fascinating watching how these kidney tumors evolve too because it is not just a size reduction, it is often a change in the internal characteristics of these tumors, and they often become much more cystic in appearance. But there is often that nodularity that probably is the focus of live disease. And I think refining how we are looking at these tumors will be important for us to make more educated decisions in terms of who probably will benefit versus who has a very deep response there. But it is tricky because there are patients that we predict will likely not have much disease left that do. And I think we have to… My hope is that as we have better PET tracers and others, we may be able to have a clearer job of discriminating.

Dr. Murray: See what is happening to the primary while you are getting that cure. Right.

Dr. Beckermann: Any difference that you see… And this might be too detailed of a question. But you were just mentioning that maybe, sometimes, the concern from a surgical perspective is what are you going to walk in or be in the operating room with after a treatment effect? So is there anything different known between operating after a pure IO regimen versus an IO-TKI regimen?

Dr. Murray: Yeah. I do not think so. Overall, I think the biggest thing that comes to be, honestly, is really the renal hilum is what you are always thinking about, the vascularity, and really the nodal status. Or if a patient had bulky nodes, I think, is where that kind of sticks in and gets scarred in from a technical standpoint. But I do not think it is necessarily different.

Dr. Beckermann: Yeah. Okay. And then Matt, I wanted to pick your brain. We have seen last year and maybe some updated data this year as well, looking at each of the frontline regimens and how they perform based on the site of metastasis. And so I know you have done and have a huge knowledge base. And I find it particularly difficult to treat patients who have bony metastatic disease. So if you have a patient in front of you and maybe it is bone-only disease, how do you think through that? You know, they are having pain and…

Dr. Matt Campbell: Yeah. They are challenging cases. And I think what we saw from kind of the summary of the bone sites across most of these trials is that the IO-TKI response rates in PFS are very similar to the general population on the trial. So these studies, particularly with cabozantinib with nivolumab or pembro and levatinib, are very, very active in bone.

And I think, to me, the patients that have dangerous sites, I really think of kind of five areas. It is really, to me, brain, liver, bone, pleural effusions that are metastatic, and then patients with peritoneal disease with ascites—those are patients we really run into trouble with early. And those are patients I worry I really have a single shot in. And those are patients I am going to either give cabo-nivo or lenvatinib-pembro to.

And if patients do not have those kinds of risky sites or if they have risky sites and are sarcomatoid, those are the patients that I am going to give nivo-ipi to because I think nivo-ipi really shines. You guys did beautiful work looking at characterizing the sarcomatoid and the rhabdoid and just showing how they do have some biologic differences between the clear cell. But I think the patients that are going to fly through are going to be really enriched in those dangerous sites of disease.

Dr. Beckermann: And do you think there’s something special about the signaling from the TKIs that have a broader TKA profile rather than a pure VEGF profile that that’s the benefit that we’re getting or from a biologic standpoint?

Dr. Campbell: So we did some animal modeling on this and we did look at axitinib, cabozantinib and lenvatinib and both, cabozantinib and lenvatinib, do appear to have a different way of modulating the bone. They actually can stop or at least temper down osteolysis in bone. And I think that this is really unique and they do appear to interact differently with macrophage populations and then also your osteoblast osteoclast populations.

And so I do think that there is something unique about how both of these agents perform in bone and we’re trying to unravel the IO component to it. And the modeling in mice has been challenging for a long time, but we’re hoping that we’re getting to a point of overcoming some of those challenges. We’re doing a very deep dive into single cell sequencing and other of bony mets and kidneys, so hopefully, more to come soon. But it’s a big area of research. Patients really suffer with a lot of pain and skeletal-related events. And I think a lot of the bone met patients that end up on trial are a little bit different than the bone met patients in our clinic because a lot of our bone met patients in clinic have really impaired performance status and challenges that make them very hard to enroll in study.

Dr. Beckermann: That’s a good point. And then before we leave frontline treatment, I want to ask David, what do you think is most exciting to you either at GU ASCO right now or just there’s been a ton of publications in the last couple of months on translational work, yours included. So would love to just hear, where you think we’re at as far as biomarkers.

Dr. Braun: So I think there’s certainly some exciting developments and I think at GU ASCO, KIM-1 has got to be, probably, the most well-developed. That idea that, again, it’s early days, but maybe, we could actually have this dynamic biomarker where we could know, pretty early on, is someone going to do great in sail through with ipi-nivo or someone needs, really, treatment intensification. I think that would be, if that validates be a really just tremendous addition to the field. The honest truth is, I don’t think the rest are ready for prime time, but I think they provide really valuable biological insights. So I think there’s a couple ways to look at biomarkers. One is trying to choose the right drug for the right patient, and I think that’s really important. The other is to say, what is the biological insight where we can really understand the patients who do exceptionally well? What are those characteristics and how we can sort of drive the biology towards that state?

And I think that’s the other thing I’m sort of excited about. If we can really understand it’s tertiary lymphoid structures, it’s these sorts of things that guide exceptional responses, maybe, that can inform, in a rational way, our design of new trials and new agents that are going to skew towards those positive phenotypes.

Dr. Beckermann: That’s great.

Dr. McGregor: I just want to add to Matt’s comment, I think one of the more challenging things we talk about is brain mets. And so how do we treat brain mets? They’ve been excluded from all the clinical trials. So I, actually, think this being one of the more interesting trials, albeit small, was we, actually, have prospective data now for cabozantinib in patients with brain mets. And we had nice retrospective data showing over fifty percent response rate and now, we have prospective data showing over sixty percent response rate in the brain with cabozantinib in patients with brain metastases. So I think that to me is very practice-reinforcing and I think, hopefully, it should be practice-informing for a lot who aren’t using these TKI’s. I mean, I think nivo-ipi just with renal cell, of the dose of IPI we use, I just haven’t seen any responses in the brain to the same extent. And so I think now, we have this pretty compelling data, I think, for cabozantinib in CNS metastases is great.

And I think it begs the question is we, probably, need to be looking at all the TKIs in the brain. Is there something there? So I think further trials saying, how can we do better, are going to be really critical because that is a very much unmet need, which we don’t have a lot of data.

Dr. Campbell: Everyone was terrified of the bleeding risk. It just was not seen. So I think size and symptoms and seizures and all these things have to be taken into account, but hopefully, we now have the courage to continue to work for. We do have an ongoing study, which is the triplet of cabo-nivo-ipi, that my partner, Jiambo Wang, has been leading for a long time. They’re hard though because de novo brain met patients are relatively rare and most patients that develop them, develop them kind of during their disease course, but not necessarily right up front.