Sam Chang: Hi, my name is Sam Chang. I'm a urologic surgeon in Nashville, Tennessee. And I have the honor and privilege of working with Dr. Kelvin Moses. Dr. Moses is a professor here. He actually has the Joseph Smith Junior directorship in urologic oncology at Vanderbilt and leads our Urologic Oncology Fellowship Program, and has done a fantastic job for years.

Dr. Moses was asked by the AUA to give actually some of the key takeaways from the AUA 2025 meeting held in Las Vegas. And he was kind enough to actually go over some of those key takeaways for us, focusing actually on more advanced disease. And there were a lot of important studies. And we've asked Dr. Moses to actually give us a recap and give us those key points. So Kelvin, thank you so much for spending some time with us, and we'll look forward to hearing what your thoughts are on some of these key takeaways.

Kelvin Moses: Thanks for the invitation.

Thank you again for the invitation to present on advanced kidney disease that was presented at AUA 2025. There were several just excellent presentations and trials that were reported out, and I'll summarize just a few and then go into some discussion with Dr. Chang.

So one of the big questions that we've had over the years is who should receive adjuvant therapy? And particularly, we do nephrectomy for patients who have T3a disease or high-grade disease and have a decent level of post-operative risk. Who do we need to treat? And so one of the studies came out of Memorial Sloan Kettering in New York. And they looked at the natural history of metastatic clear cell RCC with local therapy and to determine who should receive adjuvant therapy. And this is presented by Daniel Barbakoff out of Ari Hakimi's lab.

They had 85 patients who had metastatic disease over about a 25-year period and were NED at the time of surgery. And these patients were followed until recurrence without any systemic therapy. And they also performed genomic sequencing as well. And the items that they found that were predictive of a lower disease-free survival were those who had sarcomatoid features in the primary disease, and then had BAP1 alterations and CDKN2A amplifications.

And those who had improved disease-free survival in this cohort were those who had VHL mutations and PBRM1 alterations. And so these are very interesting findings and potentially can be targetable genes that can be identified early in the post-operative course, and then decide on who needs adjuvant therapy earlier versus later.

Another really hot topic this year in multiple cancers, including kidney cancer, was ctDNA or circulating tumor DNA. And really, how do we use it to determine risk of progression? Again, looking at patients who can avoid therapy—adjuvant—early versus those who potentially need it earlier. And this group out of Mount Sinai in New York looked at 79 patients who had large renal masses that underwent partial radical nephrectomy over a two-year period. And they all had ctDNA by Signatera.

They found that preoperatively, 61% of patients had a positive ctDNA preoperatively. And then of those who had ctDNA measured, five out of 51, or about 10%, had a positive ctDNA, and four out of those five patients developed metastatic disease. And so again, this is a really exciting advancement in determining high-risk patients. And so in the future we really need to determine if we intervene in these patients earlier than their radiographic disease, maybe we can improve their disease-free or even overall survival.

So there was a very interesting debate at the SUO afternoon meeting between surgical, medical, and radiation oncologists. And the topic was oligometastatic recurrence and clear cell RCC—how much local therapy is too much. And the scenario was a 64-year-old man who had a laparoscopic nephrectomy and was found to have pathologic T3a disease.

A year later, he had a 3-centimeter interaortocaval lymph node that was resected robotically, and this showed metastatic disease. And then a year after that, was found to have a 1-centimeter node at the vein ostium. And the debate was should we perform surgery again? Can this be radiated or does the patient need systemic therapy?

And all three of the presenters gave compelling arguments with data for each of those. Obviously, the surgeon won out in the debate—according to the audience—since it was full of urologists. But really, it's about patient selection and proximity of vital structures nearby. Any prior response, systemic therapy, any surgical risks that patients may present.

Now, there was a trial mentioned—the SOAR trial—which is a prospective Phase III comparing SABR to systemic therapy for oligometastatic disease. And what they'll report out on will be overall survival and toxicity. So this may help inform this particular question. But I want to reiterate again—it depends on what your patient presents with and what would be the best option for them.

So future studies that were discussed. So there's the PROBE trial—SWOG 1931. And this is looking at systemic therapy and delayed cytoreductive nephrectomy versus systemic therapy alone. And looking at partial response or stable disease after 9 to 12 weeks of therapy, and then they're randomized one to one to either get surgery or continue systemic therapy. And they are about one-third of the way complete.

Obviously, this is in light of the early Flanagan data, 20-something years ago. The CARMENA data that came out showing non-inferiority of systemic therapy alone. But now with our newer targeted therapies, what is the role of cytoreductive nephrectomy? So this will be an interesting one to see in the advanced kidney-cancer setting.

And then the other trial I want to mention is NORDIC-SUN. Again, similar in that it's systemic therapy with delayed cytoreductive nephrectomy versus systemic therapy alone. These would be intermediate-risk patients and deemed to be resectable after either dual IO therapy or TKI/IO after three months. And then they're randomized to surgery with nivolumab or TKI/IO versus systemic therapy.

Importantly, they are going to be doing a pretty intensive biomarker analysis looking at circulating tumor DNA, deep sequencing of DNA-RNA, and then microbiome analysis as well. And so again, these are very exciting trials that are coming. Remember to put your patients on trials with advanced disease so that we can answer these really important questions for patients. Thank you very much.

Sam Chang: Kelvin, that was a fantastic overview of some really important and exciting studies. Let's ask a question about each one of those areas of topic. The first one was looking at the possibility that after surgery, we may be able to de-escalate care and continue systemic therapy, following nephrectomy for metastatic disease or in patients with metastatic disease. There are some poor-risk features, which I think most people would agree are poor risk. And then perhaps VHL and I wrote down the PBRM1 that may be actually favorable.

So the question which you may not know the answer is, are the physicians at Memorial? Have they changed their practice dependent upon these findings, or are they, at this point, just accumulating more data, contemplating hypothesis generation, et cetera? Do you know if it's affected—what they do day-to-day now with these patients?

Kelvin Moses: So I talked with Dr. Hakimi briefly at the meeting. I'm not sure it's changed practice yet, but I think what you said is it's informing or generating the hypothesis that if we can identify these changes earlier in the course, can we follow patients with either more intensive or less intensive surveillance or earlier treatment even before radiographic appearance of disease. So I think it's really more about that—that's the first step—and then follow these patients longer.

And then really, the next step would be a retrospective study looking at those who got adjuvant therapy and go back and get that genetic information and say, OK, these patients responded better or lived longer or not.

Sam Chang: Yeah. No, I think—yeah. I think we're learning more and more as we accumulate data both ways regarding who we can actually benefit versus those who are not making any difference. We need to pivot more quickly. So along those lines, pivoting quickly, maybe too quickly. I mean, we are checking ctDNA more and more often and more and more clinical situations.

In all honesty, in urology, we're behind some of the other disease processes in basing decisions of therapy on the ctDNA results, pre-therapy, post-therapy, during therapy, et cetera. So I know you weren't the authors, but to me what would be fascinating is, OK, we have 5 of 51 that were positive with ctDNA. Did any of the ones that were not positive have any of those developed metastatic disease? And you may not know the answer to that.

Kelvin Moses: Yeah. I wish I remember because that poster was actually in one of the sessions I moderated. I need to go back. I want to say there were some recurrences, but it may have been less than 10%. It was actually a very low number.

Sam Chang: That's good. Because then obviously--

Kelvin Moses: So they were holding to it. But that is my recollection.

Sam Chang: And then I would love to know what happens to that one out of five that haven't developed. If at some point, that individual develops metastatic disease, then it really does point to—just as you said—maybe in these patients, their ctDNA, we add the adjuvant immunotherapy. We add something to these patients because it looks like they all are ctDNA-positive and they develop metastatic disease. If you add some type of IO and say that ctDNA goes negative, I mean, it's all these things that we really don't know what to do, but we're learning. And it's definitely hypothesis-generating.

Kelvin Moses: I think for ctDNA, the specificity, the numbers aren't perfect in the 50% to 70% range, but the sensitivity is high. That's like 80%, 90%. So I think that's what the info is.

Sam Chang: So then we have the future directions and we have the last slide regarding the SUO debate, because I think this is the struggle now is in these patients that 10 years ago, 12 years ago—I mean, even just after Dr. Flanagan's work, we didn't—then we were taking out way too many kidneys in patients with metastatic disease.

Obviously, before we were not ever doing that metastatic disease. It's now what do you do with interpretive interventions? Dr. Moses at Vanderbilt is well aware of. He's really our go-to advanced kidney cancer person for sure. Versus do we do radiation? Do we observe? I think that it's a struggle that we're going to see. And honestly, it's a good struggle to have. I just saw a patient today for cytoreductive nephrectomy.

And then you have to take into account the fact that this gentleman's lost 20 pounds in the past few weeks. His disease locally is worse. But we're talking retro-caval locally on that side. We're talking renal vein. So it's like when do we gain advantage? And a lot to be determined. And I think the two trials that you mentioned—SOAR and the NORDIC-SUN—I think it will be very helpful. But we'll continue to have questions for sure.

So as you are referred patients in different states of the disease, pre-systemic therapy, very symptomatic small, solitary met to someone who's had brain Mets, bone Mets, or whatever, and has responded and now just has a real—tell me what your thought process is in the metastatic disease continuum of cytoreductive nephrectomy.

Kelvin Moses: So I still follow a bit of the Flanagan paradigm. So people show up with bone and brain, just don't do well. And they tend to blow up if you operate on them. The other thing though is I will operate on those who are symptomatic specifically from disease. So large-mass flank pain, recurrent gross hematuria, clot retention, those with a high thrombus—I prefer to operate on thrombus cases pre-IO, because that thrombus, it may shrink back a little bit, but it turns into an adherent thickened rope.

And I've had to either resect cava or scrape it from the wall and hope they don't blow out. So it's a little bit of a mix. Immediately after CARMENA came out, we were doing a lot less. I would say I've picked up more over the last several years just because this local-control side of reduction and things like that.

As you know, one of the phrases we heard at Memorial and even here is some of the most aggressive surgeons are the medical oncologists. And so if they're willing to sign off on it and say, hey, we think surgery up front is great and we think it's resectable, I'll move on it because at least we've taken that off the table. Lung actually gets treated pretty well, lymph nodes, whatever. We've even done concurrent partial hepatectomies and whatever patients can deal with.

But as you know, some of our longest debates in tumor board are deciding—OK, let's treat somebody first systemically. Let's see how they do. Give them three months. Let them declare themselves. And if they don't blow up and that primary tumor is still there, then let's do it then. Because we've got to come off therapy for a while and then go back on. So you're pretty assured they're not going to blow up in that time. But if they don't respond, surgery does them no favors.

Sam Chang: Right. No—agreed. And just I think we struggle at times of how he's responded—he or she—and then oh, six months, still responding, but having some perhaps systemic treatment-related side effects. And so we try to get this window of let's avoid toxicity of systemic therapy, let's maximize its benefit. And then we try to time it so that—hey, this is the largest site of disease or symptomatic site. Then we go for it, but continues to evolve.

And with leaders like you, Kelvin, surgically treating the entire patients, it really helps move the field forward. So I know how much all of us at Vanderbilt appreciate you. But importantly, I think all of us in US Oncology appreciate all your input and your insight and your expertise. So thanks for spending some time with us today and look forward to seeing you.

Kelvin Moses: Thanks.