Andrew Hahn, M.D. Hi, I'm Dr. Andrew Hahn, assistant professor of Genitourinary Medical Oncology at MD Anderson Cancer Center. I'm here with Dr. Pavlos Msaouel, associate professor of Genitourinary Medical Oncology and Translational Molecular Pathology. And this is the Cancerwise Podcast. Dr. Msaouel, thank you so much for being here today. We're talking about kidney cancer, specifically renal cell carcinoma or RCC. It's biologically different from other cancers, and there are exciting new treatments on the horizon. For people who are new to kidney cancer, what makes RCC different from other cancers? And can you specifically talk a bit about histology?

Pavlos Msaouel, M.D., Ph.D. Yeah, and this is the No. 1 question every time that we talk about kidney cancer. It is a name that includes many, many, many different type, subtypes, and it is very important to distinguish between them. We have the most common type, which is clear cell kidney cancer. The medical term is renal cell carcinoma. Essentially that means kidney cancer. So, clear cell kidney cancer is 75% of all kidney cancer cases. And in fact, many of the therapies approved for kidney cancer, the FDA often does not specify that the studies that led to these approvals were predominantly, or in many cases, exclusively performed and applied to clear cell kidney cancer. But then we have these other 25% of cases that go under the umbrella term non-clear cell kidney cancer that represent many, many, many different types like papillary kidney cancer, chromophobe kidney cancer, renal medullary carcinoma, translocation kidney cancer. Those are just a few names. It's complex and what viewers need to know is that they should only focus and care about the one that they have, and that should be the priority. Why? Because each kidney cancer is managed and treated very differently. And with that said, I know that there have been exciting developments in how do we monitor the various kidney cancer subtypes. And perhaps you can talk to us about some of them?

Andrew Hahn, M.D. Yeah, absolutely. And to add on, when I'm thinking of histology or I'm trying to describe them to patients, I totally agree with you. And I would add into it that I like to just try to describe it as flavors of ice cream for patient. You know, it's if you have kidney cancer or RCC, it's RCC. It is kidney cancer. That's your ice cream. But there are lots of different flavors of ice cream, and there are lots of different flavors of kidney cancer. And I always equate clear cell to the vanilla. It's the most dominant. It's what most people are gonna think about. But I fully agree with your sentiment that you need to worry about the flavor that you have. Now in terms of how do we detect kidney cancer and where do things stand? Kidney cancer, compared to some of our other GU tumors, is a bit distinct in that we don't have a blood-based screening biomarker. So, for something like prostate cancer we can check PSAs, and that's a screening biomarker. We don't have that for kidney cancer or RCC. So, typically kidney cancer is oftentimes found as an incidental diagnosis. So, someone goes in to get imaging of their abdomen or pelvis for some other reason and they're incidentally found to have a kidney mass, and it leads to the diagnosis of RCC. Occasionally patients will develop symptoms such as flank pain, fevers, blood in urine, that can be the initial presenting symptoms of RCC. So, that's how the initial kind of presentation and diagnosis occurs. I think that then takes us into, well, how do we routinely image RCC and how do we track RCC over time? So, I think one key point for patients and providers is that we do not have a PET scan specific to kidney cancer. We don't have something like a PSMA PET scan. The PET scans used for other cancers that's typically FDG PET scans, they're not as helpful for kidney cancer. So, I know most of our providers here are not routinely performing FDG PET scans. Most of us are using CT scans of the chest, abdomen, and pelvis doing those at fixed intervals to monitor for response or recurrence of kidney cancer. Now, the two other spots that we'll think about imaging, although there's a lot of heterogeneity across the field even within our own group is how do you image bone? How do you look for whether cancer has spread to the bone or not? And you can do that with bone scans is one potential option, but there's a lot of different potential options there. Just know that there's heterogeneity and how you can look for it, and kidney cancer is tricky to find in bone. And then the other one is kidney cancer can spread to many different places. And so, you know, we'll oftentimes get MRIs of the brain at initial diagnosis and then potentially at fixed intervals thereafter, although that can vary provider to provider. So, I think that covers most from an imaging perspective and initial detection, although please add if there's anything I missed there. But I think going back to the histology perspective, what you know, is there a lack of understanding about some subtypes versus others, or is there kind of, what are your thoughts around that space?

Pavlos Msaouel, M.D., Ph.D. Yeah, no. Beautifully stated, and this is something that we've been highlighting for years. And it is wonderful now to see the progress on thinking about kidney cancer as its own disease, its flavor of the ice cream, exactly as you said. And to your point, for example, let's take one kidney cancer, renal medullary carcinoma, abbreviated as RMC, which is a major focus of our research program at MD Anderson. It's a very deadly kidney cancer that specifically afflicts young individuals of African descent, and we have taken it upon ourselves to make progress for that kidney cancer. We've been able to essentially double the average survival of these therapies exactly by developing tailored therapies for their disease. And to your point, for renal medullary carcinoma, RMC, we now do have a widely used blood biomarker, CA 125, that is typically used for ovarian cancer in women. But we have found that it also can be useful in about 60 to 70% of cases of renal medullary carcinoma. And again, to your excellent point about the diversity of the various images, we have found, and we have been teaching clinicians around the world, and hopefully we will be publishing more of these data soon, that FDG PETs can actually be remarkably useful for renal medullary carcinoma and some other subtypes as well. They're rare ones. This is why it is so important that we focus specifically to each patient's kidney cancer. And again, to your point, there is also now research emerging about dedicated PET scan strategies for even the most common kidney cancer, clear cell kidney cancer, even blood biomarkers are emerging. There's still research, but there is exciting developments ahead for both clear cell kidney cancer and the other subtypes. And having talked about that and about all the exciting things ahead, let's also talk about therapies. Would you like to tell us a little bit more about first-line therapies? What would you usually recommend today for a patient with kidney cancer and why?

Andrew Hahn, M.D. Absolutely. And to be clear for everyone, I'm going to be speaking about clear cell kidney cancer or clear cell RCC when I talk about the recommended treatments or the typical treatments that we're using, because this, as Dr. Msaouel just so astutely pointed out, it is varies enormously when you start getting into the variant histologies of RCC or those other ice cream flavors, you can get huge amount of variation there. So, for clear cell kidney cancer, I think first-line treatment is pretty straightforward in 2025. We have four different combinations. So, these are two drug combinations. And all of them are going to have the backbone of a PD-1 checkpoint inhibitor. People will refer to these as immunotherapy. These are not chemotherapy. These are trying to activate the patient's own immune system to recognize and attack the kidney cancer. So, that is a big part of the backbone for treatment of clear cell kidney cancer as the first treatment. And then you're going to add something else to that medicine. You're going to either add another type of immunotherapy that could be a CTLA-4 immune checkpoint inhibitor or you're going to add a pill, a targeted therapy. Again, not classic chemotherapy. There's really no role for classic chemotherapy in the treatment of metastatic clear cell renal cell carcinoma. But these targeted therapies there's three different pills we can choose from. So, just to kind of cover the names of the four different regimens in case a patient or their loved ones are trying to think what are the options. We've got nivolumab plus ipilimumab. We've got pembrolizumab plus axitinib. We've got pembrolizumab plus lenvatinib. And then finishing it up we've got nivolumab plus cabozantinib. These four treatment options have never been compared head-to-head. We likely never will. There is some nuance in who do you choose, which regimen do you choose for which patient with clear cell kidney cancer. But I don't think we'll be diving too deeply into that on this talk for today. So, then I'll flip it over to you, Dr. Msaouel. What happens whenever the first-line treatment stops working? How do next, next lines of therapy differ from those first-line treatments?

Pavlos Msaouel, M.D., Ph.D.  Yeah. And exactly to your point, while we, it's impossible to share all the different strategies that we come up with, and they constantly evolve as we gain more data. We're always very open and happy to talk with oncologists from all over the world and brainstorm and share our knowledge, learn also from their experience, etc. this is something that we were literally doing earlier this morning, communicating with people around both the United States and around the world about challenging cases of kidney cancer. And exactly to your point, you focused beautifully on the most common flavor of ice cream, the vanilla one, clear cell kidney cancer. For some of the other more rare ones, the exact opposite thought process may apply. So, for example, you said very correctly that for clear cell kidney cancer, we essentially never give chemotherapy. But then there are other types like collecting duct kidney cancer or renal medullary carcinoma where we prioritize chemotherapy. And in fact, for renal medullary carcinoma, the standard immunotherapies that have transformed the care of so many patients with clear cell kidney cancer and other cancers may actually not only not be effective, but they may actually be harmful. This is why it is so important that we specify. Sometimes patients, you know may say, "Hey, why did Dr. Msaouel or Dr. Hahn did this to me?" And then the other patients say, "Oh, they did the opposite for me." That is because each case is unique. Each patient deserves tailored therapies for their particular situation and disease. And this is exactly what also applies to your question on what we do next after the first therapy stops working, or if it never worked, then we will choose depending on the context. For example, if we had chosen only immunotherapy for a patient with clear cell kidney cancer, and now we know that immunotherapy no longer is working, then we might try the targeted therapies, the pills. Sometimes patients call them chemo pills. And I know that you have some exciting progress in your research, Dr. Hahn, on this topic. And you will be presenting some of these results at the European ESMO meeting?

Andrew Hahn, M.D. We have run a clinical trial, a phase II clinical trial called the LenCabo trial, where we randomized patients, meaning kind of computer coin flip them, to one of the two available pills, cabozantinib as one of them, or lenvatinib plus everolimus, actually two pills for that one, after their cancer had gotten worse on immunotherapy. And this was only for those patients who had that clear cell renal cell carcinoma. And we have the results of the study. I'm, you know, optimistic or hopeful that it's going to be helpful to everyone's, patient, or doctors who are treating them and really help improve things for patients with clear cell kidney cancer and hopefully make the sequence of how we give treatments clearer to providers. So, really excited to share that at ESMO. And then I'll follow up kind of back to what we were saying with the standard treatments for clear cell kidney cancer. I really think you're trying to think of like, what are the big benefits, like what's happened in the last ten years for clear cell kidney cancer, some of our mentors have been instrumental in this, you know, Dr. Nizar Tannir being one. These immunotherapies have the potential to put patients into really, really durable, deep responses where their cancer is under deep control for many, many, many years. I mean, we have patients out 8, 9 years now from these immunotherapies, and that is something that did not exist prior to these immunotherapies in 2015. So, that is, I think, something for patients when they think about what are the benefits of these treatments, what are the potentials. And then on the flip side, what are the potential harms, or like what are the challenges that patients are interacting with? I will be honest that all of our medicines, despite the fact that we like to say they're not chemotherapy, they definitely have real potential side effects. Immunotherapy can over activate the immune system and attack somebody's own body and cause potentially life-lasting side effects. And then the pills, the targeted therapies, have their own class of side effects that really impact pretty much every patient who takes them. It's just to what degree does it impact them? So, there really have been over the last eight, ten years, real benefits, but also real challenges for patients. But that being said, on the standard front, we've talked about kind of the upcoming presentation at ESMO. I'd like to hear more Dr. Msaouel about what kind of what trials do we have going on at MD Anderson for clear cell RCC that are kind of exciting novel approaches? And I'm going to set you up, but there's two that I'm specifically thinking of. One of them called the IVORY trial and then another one around cellular therapies. But tell me more about that.

Pavlos Msaouel, M.D., Ph.D. Yeah, and exactly. For the audience, it's, it's good for them to know how much it takes a village to move this research forward, including through patient participation. And one of the most fulfilling parts of doing this research, in addition to seeing, obviously, the patients respond, is the opportunity to discuss them with you and our other colleagues. We've been discussing, as you know, your clinical trial data for the past few weeks, learning from them, dissecting them, etc. And you and I have been discussing about the trials I'm going to talk to about now, which are trying to push the field forward by developing new mechanisms. Are there ways that we can crack open the kidney cancer space with new ways to treat patients with kidney cancer? And one new way is to modify antibodies. We know that we can use modified antibodies for years in cancer therapy. And in fact, immunotherapy that we've been using is a type of modified antibody, but there is a new way to modify them to target two different targets. And this new way can be used to target an immunotherapy target called PD-1. It's the same target that pembrolizumab, Keytruda, or nivolumab, Opdivo, also targets. But at the same time, that same antibody can target another target called VEGF. So, an antibody engineered to target both PD-1 and VEGF, and the idea is that perhaps that antibody can do better than the standard immunotherapies that target only PD-1 alone. And so, it's exciting to say that the first ever clinical trial to use a PD-1 VEGF bispecific in clear cell kidney cancer in the world was just activated, designed by our group with your help, Dr. Hahn, and started treating patients just a few months ago, and we're now learning from that experience. It's a wonderful opportunity for patients to get exposed to the cutting edge of therapies and for us to push the the field forward. At the same time, in addition to those engineered bispecific antibodies, and there's a lot of other movement in that space, the other big one is what we call cellular therapy. So, we take immune cells, and these can be either T cells or NK cells. These are different type of immune cells. They're essentially the little soldiers in our body that our immune system uses to recognize and attack cancer. We can take these T cells or NK cells and engineer them to make them even more likely to specifically recognize the patient's cancer. And we have been doing that in our group, both for what we call CAR T cells. So, when we engineer those cells, we call this CAR, car. And when it's engineered T cells we call it CAR T cells and then CAR NK cells, so when we engineer the NK cells. So, we have clinical trials ongoing and upcoming, including one that we'll open, the CAR NK one that will open in the next few weeks, that we are exploring for our patients. And we're very excited about those opportunities. It will, of course, none of them will immediately be the silver bullet that will get us to cure 100% of patients. However, it is progress, and it shows that there is hope, even for patients with kidney cancers that have been resistant to the standard available strategies. We need to remember many of these strategies didn't exist 10 or 15 years ago. So, even during my time as a faculty, there has been such an emergence of novel therapies that can make a difference for our patients. And exactly to this point, I would like to ask you, Dr. Hahn, how do you think that this evolution of our understanding of kidney cancer might personalize the treatment and surveillance strategies in a way that changes our practice and is impactful for our patients?

Andrew Hahn, M.D. Absolutely. From a treatment perspective, I want to highlight one thing that you just pointed out in both of those studies, which is we are really trying here at MD Anderson to try to add new tools to the toolbox with our clinical trials, meaning totally new ways of treating kidney cancer that are innovative and disruptive in a positive way. And you can hear that highlighted in both of the trials that Dr. Msaouel discussed. Dr. Tang, one of our radiation oncologists, and Dr. Msaouel have done some really nice work at trying to look at how to personalize when to intervene with treatment for kidney cancer. So, to describe a situation for everybody. There's a group of patients who will have a kidney cancer that's, that gets limited to the kidney or maybe just in the lymph nodes around it. Oftentimes referred to as a stage III RCC, clear cell RCC. And we think about using immunotherapy, pembrolizumab, for about a year in those patients. We consider it. We definitely do not do it for everybody, and there's a huge amount of debate in our field about this. Question here is: are there tools that can help us better select patients who we should and will benefit from intervening with a treatment after their diagnosis of stage III kidney cancer to keep them cured? And I think you can start to see that play out with two new technologies that are coming down the pipeline. One of them is the measurement of a protein in blood or plasma called KIM-1. KIM-1 seems to be very closely associated with the burden of kidney cancer that patients have. And then another way to track them, whether there's any residual kidney cancer present or not, or kind of residual disease. Are these ctDNA tools, these bespoke ctDNA tools, or tools that we take the tumor, we do sequencing of the tumor, and we create a DNA tool to check whether there's DNA from that tumor in the blood still present. And if you start to detect it, maybe there's a reason to intervene at that point. So, both of those, I think, are ways that we can personalize treatment and personalize intervention in the future. There's going to be a lot more coming down the pipeline. And I want to highlight another thing that Dr. Msaouel said earlier, which is going to be the personalization of cellular therapies and utilization of cellular therapies, is another opportunity there for clear cell kidney cancer. So, that all being said, we talked a lot about clear cell and what the future looks like for clear cell. What in your mind is exciting in the non-clear cell or variant histology space for RCC?

Pavlos Msaouel, M.D., Ph.D. The beautiful thing to observe now is how now people believe that we can make a difference, particularly for each non-clear cell subtype. I think we now have enough practical examples and people have seen that; indeed, we can develop tailored therapies specifically for each subtype. So, now there have been even randomized trials performed for the papillary kidney cancer subtype, which is the second most common kidney cancer after clear cell. We have the so-called fumarate hydratase-deficient kidney cancer, which often can be part of a syndrome known as HLRCC, a genetic syndrome. There have been therapies now tailored and developed for that kidney cancer. For renal medullary carcinoma, we have developed multiple strategies that have now essentially doubled the survival of these patients. And we went from less than 1% of these patients being curable to now even up to 10% being rendered disease free, essentially cured. It's not 100%, and that's what we're working towards. Get it to 100%. But that is progress. Having people now alive and some of them rendered disease free, that 5 or 10 years ago, that wouldn't be the case. It is inspiring to see, and this is what we're excited about, seeing people motivated now and organizing, including our patient advocates and patients, to develop therapies and push for therapies for each specific kidney cancer subtype. And so, Dr. Hahn, for the patients and caregivers listening now, what would you say are the most important things to know about kidney cancer and about advocating for kidney cancer today?

Andrew Hahn, M.D. Yeah, the first one I would say is get to know your cancer and understand your cancer and ask your doctor. Push him and ask questions to best understand your cancer at diagnosis. You've heard us both discuss how much variation there is in imaging, treatment, surveillance, etc., based simply upon the histology that you have. And the same is true about stage. So, it can be very empowering for patients and caregivers if they understand what stage of cancer have I been diagnosed with from the beginning? If there is a recurrence, what's the intent of the treatment? Is this treatment potentially curative, or is this a treatment that's going to help me live longer and help alleviate symptoms from my cancer? That can be really powerful for patients. And then it's always good to push. Push your oncologist. Push each of us to understand your treatment options. Because as you've heard us both allude to, there are options here. And then the final piece of advice I just give for clear cell kidney cancer is that if you've been diagnosed with metastatic clear cell kidney cancer and you're getting first-line treatment, a simple takeaway from today is that you should be getting an immunotherapy-based combination with two drugs, and that's a simple way of thinking about it. Any final remarks from you as you're thinking about the future for your patients with both clear cell and non-clear cell, or variant histology, kidney cancer?

Pavlos Msaouel, M.D., Ph.D. I would echo everything that you've excellently summarized, and I will say that there is hope. There is excitement. There is research ongoing that I believe will get us closer to one day eradicating kidney cancer for every patient, but it is going to take a village. It will need the collaboration of all of us. It will require the support of the research, patient empowerment and I have been so inspired to see how patients can organize themselves and advocate for themselves and push for researchers and changes in clinical practice that can make a difference. I cannot emphasize that enough. Everything counts. Every act counts. Every little push. It might sound little, but it can make a difference to advocate for kidney cancer research. So, it's been a pleasure discussing about this field with you, Dr. Hahn, today.

Andrew Hahn, M.D. Thanks, Dr, Msaouel. Thanks for tuning in today. If you enjoyed this episode, don't forget to follow or subscribe on Apple Podcasts, Spotify, YouTube, or wherever you get your podcast. And be sure to comment or review. For more information or to request an appointment at MD Anderson, call 1-877-632-6789 or visit MDAnderson.org. Thank you for listening to the Cancerwise Podcast from MD Anderson Cancer Center.