Exploring the Latest in Renal Cell Cancer Therapies with Dr. Monty Pal using an Algorithm

Speaker 1 Hello everyone I am Rahul Gosain. Speaker 2 And I'm Rohit Gosain. Speaker 1 And we are the oncology brothers today. We are honored to have a leader, educator, A clinician, but importantly a mentor to so many in the world of Gu malignancies. Dr. Monty Paul from City of Hope With Doctor Paul, we hope to discuss his approach to treating renal cell cancer and reiterate the current standard of care treatment options for us. Monty, thank you so much for joining us. I'm. Speaker 3 Delighted to be here. Thanks for having me. Speaker 2 Welcome Monty to Right Star into our localized disease. Before sometime, particularly before 20/21, this disease used to be surgery and observation. But of course thanks to so many patients, we now have the option of adjuvant pembrolizumab. In 2021, this was approved based on DFS data what a few weeks ago Doctor Shori presented the overall survival data. Monty your approach post surgery in localized disease for this patient population. Speaker 3 Yeah, you know I I actually think that the overall survival date is really a clincher. You know I ran a study, there are two other negative studies looking at adjuvant immunotherapy, the pembrolizumab study strongly positive in terms of disease free survival. Now we have the overall survival signal. So I think it's pretty straightforward. If you think about the landscape for patients that have high risk disease and I'll dive into that in a second. You always want to maybe discuss the options of senitnib, which we rarely use to be honest with you and pembrolizumab. But I think pembrolizumab really wins out. You know senitnib really has so much of the way of toxicity, no overall survival benefit, many conflicting studies. Whereas with pembrolizumab, I think that the data is quite unique and for any patient basically who's T2 grade 4, these were the eligibility of the trial that led to its approval T2 grade 4 or T3 and up. So it makes it really easy, it's T3 and up T2 grade four. I would probably offer adjuvant pembrolizumab and in my practice, I'd say it's about 90% of patients who actually do latch on to adjuvant therapy, very few who opt not to. Speaker 1 Monty, thank you so much for going over that something that you've mentioned. We all continue to learn so much from negative trials as well. So it's worth mentioning Epinivo dual checkpoint inhibitors were also tried in adjuvant space, but this strategy did not show any survival benefit. Also now as a generalist, we see breast cancer and lung cancer and in that space we've seen positive data on Peri OP approach particularly with immunotherapy. But this approach also did not translate in any obvious benefit here in RCC based off PROSPER trial, a phase three study using nivolumab. Coming back to what's available today, Monti, any utility in checking PDL one score to predict the response of premaritalizumab for these patients? Speaker 3 Yeah, really not. I mean if you look at the forest plots from this publication across the board, you know, if you look at the low risk populations versus high risk populations, if you look at PDL one status, if you look at you know things like gender and so forth, I mean everybody really seems to stand to benefit at least to some extent with pembrolizumab. I've heard the argument to suggest that maybe in that lower risk stratum of patients, you may not offer the drug. But again, you know, whenever we're doing these subset analysis, I just worry that we don't really have the power to rule against using the agent in that setting. So I I'd really hate the idea of short changing impatient, the ability to receive an agent that could improve their their longevity. Speaker 1 Thank you, Monty. And again, even before we go any further, for the listeners, can you define, we've mentioned these terms of high risk, but can you define favourable intermediate and high risk? What makes those characteristics? Speaker 3 Yeah. You know, in the localized disease setting, it's a totally different ball game in terms of defining the patients. Typically, we would say that those patients that are T2 or T3 who meet eligibility for the protocol would maybe be an intermediate risk range. The patients that have resected metastatic disease would be the highest risk folks. You know, I think that the, the data really suggests that across the board, you know, there's a good application for pembrolizumab here. I will say that, and this is 1 nuance. The one patient that you might want to be mindful of is the patient who has resected metastatic disease that's years out from their original surgery because those patients were not necessarily included in this trial. The patients that had resected metastatic disease in KEYNOTE 564, the study leading to the approval we're seeing here on your screen, it is actually only exclusively looking at those patients with resected metastatic disease within one year of their original surgery. So if the patient's eight months out, ten months out from their original surgery and they've had metastasectomy, by all means consider this. If they're three or four years out, maybe just observation in that case. Speaker 2 Thanks for covering that. Let's dive into metastatic space though there are multiple treatment options available, which is certainly a good thing for our patients here. However, when talking about surgery, any thoughts about before we start on systemic therapy, your management with regards to surgery here? Speaker 3 You know, I have to tell you, you know, for my clinical practice trials that were done in the TKI era, studies like Carmina and Sertime, they really suggested to me that, you know, surgery has a very unclear role in the context of modern therapies. And truth be told, we're repeating some of those trials. There's a trial called PROBE to evaluate the role of cytoreducting nephrectomy in the current era of therapies like the ones you're showing here on the screen today. But until we get an answer from that, my suggestion is focus on the synthetic therapy 1st and think about surgery later. Now there's always going to be those absolute indications for surgery. If the patient has pain, if they have bleeding or if they have perineoplastic syndromes, it's kind of a the three classic symptoms we always learn about in in our medical training. In those cases, you definitely want to get the urologist on the phone and get that kidney out. Otherwise, I think the lesson that I've sort of learned over the past couple of years is you've got time. You can start with your preferred systemic therapy and make surgery a bit more of an afterthought. Speaker 2 Thanks for covering that. Now, when you talk about preferred therapy, what has your paradigm been and how do you decide on the algorithm? Speaker 3 Yeah, you know, it's a complex algorithm. I like what you have sort of listed here on the screen. You know, for the most part, you know, I think that any one of the doublet regimens is reasonable across both the favorable and intermediate risk setting. And I'll tell you my thinking has actually evolved since we just saw each other in San Francisco for ASCO Gu, you know, I will say that before I used to be a bit of a purist, I would offer the TKIIO combination. So specifically Cabo nevo LED pembro or axi pembro, I'd offer those to favorable risk patients and for intermediate and poor risk I'd add to the consideration of volumab and nipulumab. After seeing the eight-year data for navolumab and aplumab, I'm actually willing to consider it for favorable risk patients too. You know, provided you can get payer approval and everything it is outside of indication. But you know the long term data really seems to suggest that in favorable risk populations it works quite well too. So I think any one of those doublets is appropriate across the board, favorable or intermediate risk. What I usually think about in terms of clinical application though is you know what sort of situation is the patient in. If the patient has dominant bulky disease that's symptomatic, I know they're going to need a TKIIO regimen. And one thing I always quote to patients is that if you put 100 folks in a room and treat them with these regimens, you're only going to have five or six that progress immediately on a TKIIO regimen on the and you'll have about 70 to 80 that respond quite well or 70 or so that respond quite well. On the other hand, if you use IOIO with the volumabinipilimab that response rate falls to around 45 to 50% and you have about 20% of patients with primary progression. So those are some of the circumstances that I consider and and deciding on what type of regimen to use Frontline. Speaker 1 Monty, thank you for covering that. Monty now with pembro taking a step back approval in adjuvant settings if the disease was to recur while they're on adjuvant treatment. This is high risk. This is bad, bad disease. What would your approach be in that settings? Speaker 3 Yeah, it's a really complicated question because I don't think we have a firm answer at this point in time. You know, I think a study that me and one of my colleagues Tony Chiwary worked on called Contact Three really suggests that there may be dubious benefit in using one IO after another. The way that I sort of extrapolate that in this setting is that if you have a patient who's on adjuvant therapy with pembrolizumab, it probably doesn't make as much sense if they've progressed in a really short course either during therapy or maybe within a year thereafter to continue IO based treatment. So for that sort of patient, I would typically use Kaposantinib monotherapy. Speaker 2 Interesting. Now before we jump into the second line, any particular role of NGS or circulating tumor DNA, especially when we talk about this era of personalized medicine? Speaker 3 Not at this point in time. I mean it's a great question. And I I do think that's something that we're looking at in the context of a trial that Brian Rini's running where we're actually putting patients into buckets of therapy on the basis of their genomic profiling. You know, I I think for the time being and I, I really want to be very clear to your, your terrific audience here. I think you can be somewhat dogmatic in the treatment that you assigned. I would say that I end up prescribing most of my patients cabazantinib, devolumab in the frontline setting. You know, the reason being again higher response rates, lower rates of primary progressive disease and in addition to that, we see that amongst the other TKIIO regimens, the quality of life data really seems to stand out. So you know again with Cabo nivo, we're actually using a lower dose of cabozantinib 40 milligrams than what we would use in the salvage setting of kidney cancer which is 60 milligrams. So I think that really contributes to the side effect profile and the quality of life profile that we see. So I'm not using any biologic factors. I'm really just using clinical Hakimen and I would say Cabo nivo is what I tend to side with for the most part. Speaker 1 And again, as generalists, it's so important for us to know all this because we're seeing Kavel being used more and more in other disease sites. There's a phase three study at SML 2023 for neuro endocrine tumor with Kavel zantanib. That's positive. We're waiting for approval there. The other Ttis mentioned here, linvatanib is approved for HCC. So again, in the community, we're very comfortable using or managing some of the side effects of Linvatanib. Speaker 2 And just and just talking about the side effect profile, how similar the Tkis are to immune checkpoint inhibitors toxicity, Monty, any particular clinical pearls especially when we are tied in when both of these are being utilized and have similar side effect profile? Speaker 3 Yeah. And it's a great question. There's some side effects that I think are pretty easy to tease out. So let's say I have a hypothetical patient on Cabo Nevo and they start developing hypertension or hand foot syndrome. Those are things that we probably know from experience are going to be related to the Cabo Zantinib. On the other hand, let's say they develop significant itching. You know we know that that's likely related to the immunotherapy component. The really tough part is when they develop overlapping side effects. So things like diarrhea and hepatitis can be really challenging to suss out. And the way that I think it's probably most practical to do that is to stop the TKI. If you start seeing the toxicity to dissolve liver function tests improving, diarrhea improving, then that's usually going to be the the TKI being the culprit. On the other hand, if those issues continue to escalate you you're definitely probably dealing with an IO based toxicity. Speaker 1 Again, getting comfortable in managing all these combinations, be it immune checkpoint inhibitors or TKI is so important. Monty moving on for a second line. So let's say they got IOTKI and now the disease has progressed after first line. Your thoughts moving forward? Speaker 3 Yeah. So there's so many new options in this setting. So let's take again that hypothetical patient. Again, I'm typically starting with KABO Nevo. If they actually are moving on to second line therapy. If I haven't used KABO Zantanib, that would probably be my mainstay. But bear in mind, I've I've used that already. So I've actually started taking up an algorithm in which I'll use Lenvatinib and Everolamis for a patient who is A really robust and B needs to evoke a quick response to therapy. Let's say that patient's really symptomatic has high disease burden linvatinib and never roll in. This I think has high response rates in the ballpark of 45%. And I would say that it also it is one of the tougher regimens. So that's why it's it's really not for the patient who's got borderline performance status who may not be able to tolerate the colitis and other issues that come with it. On the other hand, if the patient's really frail or if I think I've got more time to evoke a response, I might consider using tevozinib. And I know we often times relegate tevozinib to 3rd and 4th line treatment, but I think there's insufficient evidence to say that you know it probably works and the population of patients that has already received TKI and IO based therapy, Belzutafan is the newest player on the block. It's a if two inhibitor very distinct mechanism in kidney cancer but really does fall along the VEGF pathway to some extent. I'm actually pushing that back to 3rd and 4th line therapy only because the time to response is very slow. You know, we don't get that immediate response that sometimes we need in the salvage setting. And in addition to that, you know, I I think that the response rate is more modest than for instance what we might see with linvatinib and everoleness. Speaker 2 But we tend to rely on limbic that and have rely medicine community as well. But you know when talking about third and fourth line, we are a bit hesitant because of the side effect profile we're not used to. So any particular clinical pearls for tevozinib and balzutafen, especially how balzutafen is so new here? Speaker 3 Yeah, Tevozinib is an agent that I think is quite well tolerated amongst all Tkis. You might see with it, for instance, higher rates of hypertension. But having said that, lower rates of fatigue, lower rates of hand foot syndrome, lower rates of diarrhoea and the hypertension, I think that we all have some comfort level with managing you know with frequent phone calls and what have you and we can get that under good control. You know with Belzuta fan the principle is very different. I would say that the agents very well tolerated, but you do have to be quite mindful of anemia that it can induce. There's also reported hypoxia with it, although I have yet to run into that in my practice. The anemia does require some diligent monitoring. I would say that especially in the salvage setting where you might already start seeing the hemoglobin creep down to 9 or 10, you've got to really make sure the patient's not sinking far below 8. You can transfuse, you can dose reduce. EPO is not recommended in the label for Belzutifan, but it's something that a lot of my colleagues in kidney cancer do. I'm a little reluctant to give growth factors just because the potential sort of pro angiogenic, pro cancer effects, but some of my colleagues do employ that strategy. Speaker 1 Monty diving into that a little deeper. So Anemia is responsive once you decrease the dose for Belzutifan. Speaker 3 Exactly. Belzutifan starts at a dose of 120 milligrams. If you start seeing the anemia approach, you can actually decrease to 80 milligrams and then to 40 milligrams. I've had that experience many a time in clinic and if you really follow that patient closely, I think you can probably get them on a comfort level where the anemia is subdued. Speaker 1 And one thing that I want to mention, when we're talking about Balsutafan based of Flight Spark 005 or tevazanib, these were the only two drugs that were studied post immunotherapy. Everything that we have ends up being a little Gray area, but the data for Balsutafan and tevazanib based of PFS is when they had progressed on immune checkpoint inhibitors. Speaker 3 That's correct. Exactly. About 25% of patients, the tevazanib study had gotten prior checkpoint inhibitor more in the case of Balsutafan. So you know there's a good case to be made for these agents being appropriate post IO therapies. Speaker 2 Thanks for covering that, Monty. Any last thoughts for us in the community setting when treating RCC before we close here? Speaker 3 You know one thing that I will send and thank you for giving me such an amazing forum to do this. I I love your program. I I would say that it would be really key if you start seeing patients with non clear cell Histology to get us on the phone because that's a subpopulation of patients where there really is no obvious standard. But we do have a number of clinical trials enrolling. There's a trial called Stellar three O 4, which is open countrywide. It takes papillary translocation and patients with unclassified tumors as well. And the study randomizes to Snitinibor, a novel TKI called XLO 9/2 plus nivolumab. There's also a study called PATNET 2, which builds on a study I published a couple years ago for the disease. It's Cabo plus minus otezo and papillary. That's one place where we'd love to see that patient up front because those are frontline trials that otherwise we miss a window to accrue to. Speaker 2 Certainly, Monty, thank you so much for sharing all this knowledge and going over the current standard of care practice in renal cell cancer with us today. For our listeners, let's recap. In this discussion with Doctor Monty Paul from City of Hope, we have covered the current landscape and treatment options for renal cell cancer. Speaker 1 Now with overall survival benefit with pemberlizumab, this remains our standard of care option for intermediate and high risk patients in adjuvant settings. Speaker 2 Then we focused on different first line treatment options including checkpoint inhibitors and combinations with TKI such as Linvatnib, exetnib and cabozantinib. We also had a chance to touch on Balzutafan and Tvozoneb in second to third line treatment options and beyond to stay up to date. Also make sure to check out our full discussion of prostate cancer and bladder cancer. We are the oncology brothers.