Challenging Cases - Treatment of Renal Cell Carcinoma (RCC): Dr. Pedro Barata

Hello and welcome back to the oncology brothers podcast. I'm Rahul Gossein here with my brother and Gohost, Rohit Gossein. We're back with our challenging case series where we touch on real life cases that we hear about from our community colleagues. Goal here is to touch on real world application rather than have an academic debate around how the field is going to evolve over the next five to 10 years. Today we're focusing on kidney cancer. And for this, we're excited to have Dr. Pedro Barata, a G.U. medical oncologist from University hospitals. Pedro, thank you so much for joining us. Thanks for having me guys. Great job. What are you doing with the platform and happy to be here. Pedro, welcome. Over the next few minutes, we want to touch on two cases. First one is we are trying to understand in the metastatic space, how are you picking amongst the frontline options that are available. And in second one, how are you deciding on your treatment of choice in second line and beyond? All right, let's move along into our first case at hand. That is 71 year old gentleman with past tobacco history, now with multiple bone lesions, lung nodules, and large kidney mass. The patient did undergo lung biopsy, which was consistent with metastatic clear cell RCC. Pedro, as part of your workup outside of clinical trials, any role of NGS to guide your treatment options. For the common practitioner, we currently using NGS mainly for research purposes. You can make the claim in the fractures settings for certain alterations that may help you a little bit to take a stronger weight on some options. I'll give you an example. If you find TSC1 or tuberous sclerosis gene alterations or even P10, there's some data suggesting that you may benefit from M-Torin inhibitors. Again, we're talking late line. For most part, we're not taking what is reported on NGS, which includes, as you guys know, we call it now all genome sequencing, that includes the NA alterations, RNA sequencing data, as well as the protein expression. But if you were to tell me you have gene expression signature information, would that help me preliminary face to data says, probably yes, without that available, which most of us do not have access to it? I would say that's probably reserved for research purposes. So we do it, but we're not waiting for those results to define the front line option that patient is going to get for the most part. For Dino, you said outside trials, but again, NGS can help us make sure that we're partnering that right patient with the right trial as well. So something to keep on our radar. But coming back to this case here, Pedro, our options are IO with TKI, where we have few options. An evil cabo, Pembro XA, Pembro LEN, and then we also have the option of that dual checkpoint inhibitor, ipin evil. We also have single agent TKI, but single agent TKI is something we're not commonly using in our practice. But for this case, how are you picking one doublet over another? But we in dual checkpoint inhibitors versus IOTKI, how do you make that decision? Right. So just a reminder, as we stratify these patients with all the imperfections of the nomograms available, this is a patient who presents with synchronous metastatic disease. It's a patient that has laboratory abnormalities as a consequence of the cancer until proven otherwise, including anemia. Maybe there are percalsemia. And as a patient, it sounds to me that he needs treatment right away. So he does have probably poor risk at this time if you're going to consider the calcium, the anemia, the time from diagnosis to treatment. So you already have three factors right there, right? With that said, we have a number of trials that we've been talking for the last several years based on immunotherapy, whether it's IOIO, as you said, ipin evil, or an IOTKI option, usually thinking of carbon evil, acypemboreal, lamphemboreal. So I would say all of those four options would be the preferred way to go compared to TKI monotherapy, which is not recommended in a school standard for most patients. So that's be the conversation here today. There's pros and cons of doing one or the other. I could make the cases you know in all the conferences we had a lot of pros for IOIO and the other folks who are defending IOTKI. I think if you look at even the immunotherapy consensus, every time you're getting closer to the typical patient who has very symptomatic disease, you really want to minimize the chances of in success of the first treatment. If you get the sense that either works now, you won't have a second chance to control the cancer, you'll probably be thinking more about the regimen that gives you higher response rates, higher tumor control, less chance of progression as best response. So that would be an IOTKI high. If it's okay to handle the 20% PD as best response, you can make the case that epinevo or the f-circometoid features where you increase the chance of success to epinevo. That's the situation where epinevo will be used in many cases. So I would say I do quite a bit of IOTKI. I also have gene expression signature data available at time. So I like to think that helps me a little bit, but in the absence of circometoid features, very symptomatic patient, a lot of disease, so high tumor burden, I would be very comfortable doing something like Kaboenevo or LEMPAM in this patient. As a good performance status, why Kaboenevo LEMPAM? Because we've seen the lowest PD rates with those two combination regimens, within a solid tumor control around a year and a half or so. And so I'll be comfortable with that, and this is what I use in practice as well. With that said, for intermean poor risk, patient considering epinevo with scans, maybe much earlier than the three months that folks do in clinical practice, just to make sure you're not missing out those early progressers. It would not be unreasonable either. And of course, we're still debating what can we use to make that decision even better. - Indeed, as you mentioned, circometoid features, IMDC criteria, and with regards to some of the normal grams, IMDC criteria we still use for prognostication purposes. And past we were using that for decision making purposes to decide on the treatment approach where NIVO-IPI was only reserved for intermediate and high risk. But we have seen that at the tail, at the end of the curve, survival advantage, even in favorable risk group as a result, one can utilize NIVO-IPI in favorable choice there, but also particularly tying in the circometoid features, relying on NIVO-IPI certainly way to go. And Pedro, you mentioned with regards to the high responsiveness, where you will utilize IOTKI combination, and you said NIVO-IPI, Pembro, Len, or Pembro-Axi, Pedro, if you're not relying on dual checkpoint integrators, and only focusing on IOTKI. How were you deciding which IOTKI combination to use, and what data do we have to support that? - Yeah, so I mean, I think it was Tom Paul who said it, at least the first time I heard it, and a lot of us have repeated that over time. It's very important. There's a learning curve with all the regimens, and I think it's important if you know how to use one, use it very well, and that includes managing toxiccy, in a proactive manner, the treatments that work are those that patients are able to tolerate, and that's important. With that said, I do think that when we look at Cappus Antony or Lev Vatonyp, I do think that among the most effective agents out there, I find personally, I find the balance of efficacy and tolerability with Cabo Nivo to be probably close to the sweet spot. Remember, we lower the dose of Cabo in the combination, which is different from the monotherapy. So we do 40 milligrams with Nivo. For Lev Vatonyp, we actually went up a little bit, right? 20 milligrams of lab and PEM. So I find a lot of patients not able to tolerate that in clinical practice, and for Axi, we go with the same dose as monotherapy. It is true that you can't try to just need that. So I think the experience with a combination is important. I tend to prefer Cabo or lab as a backbone for the TKI in a sense that we've seen very low progressive diseases as best response. So that gives me a little more comfort. I'm used to use them. Most of my patients will be seeing both Cabo and Lev Vatonyp during the course of the disease. And so I do think whatever you're using, you should optimize the use as much as you can. So that's to me is important. As you think of tolerability, those adjustments, proactively managing side effects, et cetera. - You know, a few things to reach right here. We all have that preferred option, or whatever we get comfortable with. My go-to also ends up being Cabo and Lev Vatonyp, just because that Lynn Vatonyp dose is something I struggle with. Then when it comes to exit to Neb, to me, that's a weaker TKI. And while we were talking about those saying, Pedro, you mentioned this, when we're using Lev Vatonyp, the dose of Cabo's antenna is 40 milligrams, when we're using that as a single agent, the dose is 60 milligrams. Pedro, can you broadly touch on some of the side effects we have to keep in mind where the IoTKI combination and on the other extreme, we'll do a check for an inhibitor. So when you think of IoT, maybe let me start with IoT, just because the other ones might have a little bit overlapping talks. But, you know, so for immunotherapy, at this point, it's not a surprise for most folks, right? At this time, you've been using check inhibitors for all over a decade, right? So immunotherapy related adverse events are well known. They go from fatigue, usually a little bit of nausea can happen, I re-assess some GI there. Then you have the aches, join aches, muscle aches, so my allergies are trauges. You can have the endocrinopathy as well, that's important, that includes thyroid often. You can see liver, atoxicity as well. And then less often, add organs like lung, it's at right, adrenal, we start becoming really good and having clinical suspicions for adrenal insufficiency or even pancreatitis, right? So all those things can happen down the line. They're not those related and patients can develop those side effects even after being off checkpoint inhibitor. And the combination gives you more of those compared to IO. monotherapy. For the IO TKI is what I said plus the TKI based profile which is basically high blood pressure, hand-food syndrome, GI alterations, whether it's nausea, diarrhea, stomatitis, taste changes, etc. I think some of the TKI's give you more of this than others, right? So depending on the TKI that you're using, you will find more of this versus the others, right? Like a classical example. We're not using a front line, but if you were to think of Tivasana, it says to be a very, very well tolerated TKI, yet high blood pressure happens of 20% or so of the times. If you think of hand-food syndrome, excuse me, you're probably thinking of different TKI's. You can see that with Cabo, even Lamb and Axi. So it depends the TKI you're considering, but that's classical. Now some of these side effects can happen with either diarrhea, fatigue, even nausea. And so for those cases sometimes the rule of thumb is if we hold a TKI in a goes away within a few days, which follows the half-life of the TKI. You've got your answer, and that means you don't need immunosuppression because it's not an immun-related adverse event, rather as a TKI based. And that's maybe the last piece is knowing the half-life of a different TKI, helps us to read the profile and how to handle those side effects. In addition to all that, just reducing the dose, because again, a lot of these side effects are dose-dependent as well. And Rahul, when you were talking about exetnet being rather a weaker TKI, why we tend to also utilize Lennvatnebin, Cabo's at Nebin community practice because we have ease of these with other tumor types as well where Cabo is also approved in Neuron-Dokran tumor or HCC and same thing for Lennvatnebin approved in HCC and endometrial cancer too. Right, I know Lennvatnebin is approved in endometrial and HCC, but even there that high dose inside effects are pretty neat. I promise we'll get to that second case for Rohit. What is your preferred TKI Iocombination? Right, Rahul. For the reasons that we just talked about, my combination is, again, Nevo-Cabo as well in this setting. But again, that patient-shared decision making, tying in the side effects still is a very important part of the job. It's absolutely. Just one last thing, maybe the other reason for us to do Cabo Nevo-Lev-Pam, which I think is a strong one, is not always, especially in the community, we do understand the subtype and we do have data for both Cabo Nevo-Lev-Pam for non-plurcell subtypes and with activity. And so that's another reason for the subtype, who might not be as comfortable with the RCC subtype beyond Clurcell whether it's papillary or even translocation, it's unclassified, etc. You know, we do have the ability to use those, we data to back it up, which is another reason that I find common reasons for folks out there to considering one of these two combos. But I agree, I tend to use Cabo Nevo, nothing wrong with Lev-Pam, they're very active options. Now, Pedro, what we've talked about here is front line de novo metastatic disease. How about that patient if the disease was to progress after or while on adjuvant pemberalism app? This is going to get very interesting because we just saw pemberalism app, Belzudefana-Pru as well. So in that recurrent relapse disease, how are you deciding on your next steps? Yeah, so again, it's obviously a long conversation and it depends on a lot of things, right? So what patients receive previously is important and taking the patient's side for a second year, because that's another level, I think that's very important. So what patient receive is important, right? And maybe on that we'll just say we now have two face retrows that remind us that doing a salvage pd1-pd1 is a bad idea. When checkpoints emerge, we thought we should just give them over and over and over again and maybe we abuse from that strategy, even with EP, that is debatable, responses at best are 10-15% in the salvage setting. I do it for very selected cases, but the message overall is do not salvage a checkpoint inhibitor with another one because we don't have it suggesting that's a good idea. So that's the first message. What patients receive before is important? We're considering TKI's that are approved also in the refractory setting. So if you got Cabo Nivo in the front line, Cabo is a very solid option by itself in the refractory setting. That's probably not going to be my option. The same is true with LAMF PAM and I guess they might trigger a new debate around whether or not we would consider LAMF Bell later on and we can maybe talk about that later, but I probably wouldn't drop the PAM and bring Avrolimus, but it is LAMF available in the refractory setting as well. We have Tivo and Axi. So I would say that's probably the least of things that I can see there in I guess the refractory setting, Cabo, Lev, Av, Axi, Tivo, and we just saw data from LAMF Bell as I said. So it matters how you got there. You also matters how you progressing. All legal progressive, meaning most cases under control, one or two of the disease are growing. We should think of local therapy for those sites of metastasis because you can buy you more time, stay on the same line of treatment before moving on. And of course, finally, it's extremely important to talk to the patient and understand the goals and understanding how much they're willing to tolerate or it's actually what their objectives are. Are we looking for responses or are we looking for tumor control would be able to actually leave their lives. And I think that's what the No-Ans conversation and discuss around the different options plays a huge role in that site. Patient shared decision making is always the key. All right, moving along into our second case. Here we have 74 year old retired teacher with metastatic RCC, where here patient was started on Nevo EP on progression, started on KaboZantnep. Pedro here, we would love to hear your thoughts with regards to sequencing. And how are you picking amongst your second TKI options available? So just to remind her, I always like to think on the trial data and see what the disease is doing compared to the median. So in this case, 14 months of EP Nevo, it's a little bit beyond the median. So this is not a tumor considered resistant compared to checkmate to 14 data. So just making a note, this patient went on second line KaboZantnep out. I still the winner in this setting. That's what most of us do in clinical practice. So nothing unusual here. So I think that's appropriate. There's a debate whether or not we should consider lab F. There's some face to data, including data from our colleagues from Anderson comparing lab F of KaboZantnep. That would be an appropriate option in my opinion as well. In some situations, especially frail patients may not be tolerating Kabo 6 milligrams. I don't think is wrong to think of Tivasana as a first TKI in that setting. We'd look at the data from TNIvo 2, tumor control with Tivo, monotherapy was 9.2 months, the median on that study. And so for some selected individuals, I wouldn't the Tivasana as an option. But I would say for most cases it would be Kabo. And then your question I believe is once you progress in this patient did 10.5 months on Kabo, I would say it's really what I would expect. If I were to guess, I would say 10 or so a little bit less than a year. And that's exactly what we're seeing here. So it's almost exactly like one anticipate. So we're really talking about third line. And in third line, we look at the use by the community teams. It's really, you know, we have some lab F. We do have Tivo and we have Belsutifen. And I think it's around 20% or so, which one of them? And there's pros and cons of doing one or the other. I think folks are trying to learn how to use Belsutifen. Definitely a tolerability profile that's different from the other TIKI's. I alluded to Tivasana being the past. I think it's a clean cut here based on the Tivo 3 data that supports the user Tivasana. I wouldn't think to use Axi as a wrong option. I think that would be reasonable whether now or later on, probably I'll be playing with that when thinking where the lab VF would come to me. When I use LVF, I have a low threshold to drop the environments in Kippel and VAT. And as I said before, I try my patients to see both Cabo and lab at some point. And so to me, that's really the conversation around preferences, profile of the medications, thinking of those options out there. This space is starting to move quickly. We have immunotherapy in adjuvant settings. Now we have immunotherapy with Belsutifen in adjuvant settings. Then in refractory settings, we also have data from Lights Park for Lennvatin and Belsutifen. Here for this particular case, I think Cabo's antenna was very reasonable. When it comes to Belsutifen, Pedro, I know you alluded to some side effects that we have to keep in mind. Hypocrisia, Anemia, those are the things that should be on our radar. And again, sequencing IO IO, Cabo, and then perhaps Belsutifen Lennvatin or patient where you're giving IoTKI a front. And maybe that Belsutifen Lennvatin might be your second option. Pedro, I know we're short on time here as we start to close. Any final thoughts here for these two cases for us out in the community settings? So this is great. I agree with your algorithm that you just described. I think there's a number of messages here, right? Not all patients are the same. I think knowing the data helps us a little bit understanding how to read the disease. The pattern of progression is important, knowing the options because look, everything we've talked came up in doing the last decade or less than that, actually. So it does require a good level of all the data out there to be comfortable offering treatments that are contemporaneous and are the higher chance of success compared to what we had all the days, I guess, sort of speak. So I think that's important. You mentioned new regimens are coming to play. You know, the Bels combos did absolutely required learning of using that, you know, which is something we're not really used to. Talk about epoxy, talk about maybe the use of Epo, for example, which is something that I own colleges in general. I'm sure you have to cover such about this in the past in prior podcasts. Is something that doctors tend to be against it, right? I'm sure that's the same with you guys as well. You've been hesitant. Right. Yeah. So, you know, the good news is we might have better news coming up soon, sooner or later. And as the field evolve, it's really important to understand what the data tells us about what not. to do, we talk about not considering IO salvage and on the other hand, what options are out there that we should think when we have a patient in front of us. You know, on our end, we are walking this fine line between efficacy and quality of life because the treatment here is with palliative intent, be it with Nevo Cabo up front or it be Nevo as a dual checkpoint inhibitor or in later refractory settings, if we get LEN and Balsuda fan data, we have to keep these side effects in mind and the efficacy data in mind. Petra, thank you so much for walking us through these two cases and appreciating the current standard of care in metastatic RCC. For our listeners, let's go over a quick recap. In today's challenging case discussion, we touched on two cases. First, we've newly diagnosed RCC where the challenge is picking that right combination treatment up front when we have options of dual checkpoint inhibitors or multiple TKI IO combinations. Where we have strong data that first sarcomatoid features, dual checkpoint inhibitor is our preferred option. When it comes to majority of our patients with a heavy tumor burden or when we're looking for that quick response, we often lean into IO TKI combinations. During this case, we also touched on the dosing and importantly side effects that we need to keep on our radar. Rohit, what are you walking away with? Right, Rohit, from the get go, even when we are picking that front line treatment options, we are often thinking about what next. How are we going to sequence our available treatment options here? So picking that right treatment up front is important. In our second case, we talked through what to do if the disease was to progress. Here the disease was exposed with epineval combination up front and then cabo. Again, keeping that our treatments here are with palliative intent. We walk through our available options in this space and how the sequence could look different or perhaps the same if we have combinations such as Belzudafan and Linnvatin and become available here. Thanks so much for tuning in. Make sure to check out our other challenging case discussions, treatment algorithms and conference highlights. We are The Oncology Brothers.