How to Treat Renal Cell Carcinoma (RCC) using a Treatment Algorithm with Dr. Katy Beckermann

Intro Hello and welcome back to another episode of the Oncology Brothers Podcast. I'm Rohit Ghosain and with my brother and Co host Rahul Ghosain. We are practicing medical oncologists out in the community and our goal here is to keep our fellow community oncologists up to date in this ever evolving field of oncology. With that in mind, you're diving into the world of renal cell carcinoma, RCC, and we couldn't be more excited to have Doctor Katie Beckerman, the Medical Gu Director of Cancer Research at the Tennessee Oncology with us today. Katie, thanks so much for joining us. Speaker 2 Thank you so much for inviting me. It's a pleasure to be here and chat with you both. Speaker 3 It's great to have you, Katie. I'm eagerly looking forward to hearing your thoughts on what's working in RCC and importantly, how can we sequence our available options to do the best for our patients. We'll start off with early stage disease touching on the adjuvant space and then switching gears to metastatic space as we've seen a few updates and approvals here. Early stage RCC Katie, can you touch on your treatment paradigm here in early disease as we now have pembrolizumab available based off Keynote 564 study after surgery? Speaker 2 Yeah. Over the last year we've seen the initial recording for Pembro and the adjuvant space for ADFS benefit and then it also came out and reported on OS benefit which really solidified the benefit for our patients in the adjuvant space. We know we have the most data, should only data for patients who have clear cells. The trial included patients who had T2 disease if they had grade 3 or 4. But what what we basically see is that the more aggressive disease, the more likely the patient was, you know, to invest. Based on that. I will often use a kind of risk of recurrence, talk to them about the potential side effects, which unfortunately can be lifelong from pembrolizumab and try to have that personalized session with the patient sitting in front of me. Most of the time I'm offering this to patients who have stage 3 disease, higher risk, maybe IVC thrombus for sure conversations with patients who have lymph node involvement or that are M1NE D We know from the metastatic setting, patients in RCC who have so much weight features and have more of an enrichment. And so if I see that on the test and that also kind of gives me the inclination. Speaker 3 Katie, any role of PDL 1 testing? Speaker 2 You know, we just haven't gotten that to work at RCC. There's maybe a hint that it helps to enrich. We still have so many patients who ultimately will have a response and BPDL one Nexus. So currently you think kidney cancer you do not have to think about PDL 1. Speaker 4 And I think we've harped this on based on multiple studies and PDL one again is not the best marker, but we'll see how some studies play out. I want to reiterate some of the things that you mentioned, Katie, with regards to the keynote 564 based off which pembrolizumab inactive and setting was approved was T2. Speaker 1 With high. Speaker 4 Grade or circum employed features T3T4 or no positive disease. As a result, this is now the standard of care for its intermediate OR. Speaker 3 High risk breaching. Speaker 4 Population Katie, before we move on into medistatins, in terms of surveillance scans, what is your go to modality and. Surveillance scans When do you? Speaker 4 Rely on bone imaging at all in early stages. Speaker 2 When I'm doing surveillance scans I closely align with the NCCN guidelines. Often the type of scan I'll use is dependent upon because some of these patients may have CKD either post nephroctomy or due to other common abilities. If I am not able to get good imaging modality because of knee function with ACT with contrast then I'll often go to an MRI. As far as the the bone stands per NCCN guidelines, it's not not a recommended unless the patient is symptomatic. When a patient comes in with any sort of symptomatic complaints, get that I. Speaker 3 Promise we'll move on to metastatic space after this, but are you using CT DNA here or at all in RCC outside technical? Speaker 2 I'm not yet. I'm really excited for it. And I think that you asked her this year and at several of the other conferences we're seeing some really exciting developments. It's just been that in kidney cancer, it's not been a high shedding tumor like for example where I'm able to use it more predictably with urothelial carcinoma. In my experience, knee cancer can just sort of have false negative And I, I think also that there's going to be newer technologies that maybe give us better readout. So I hope more more CTDNA or hypermethylation or other other ways to do non invasive testing, you know coming. Speaker 3 We're now on to metastatic and ACC. Metastasis and ACC If we have a few options here, dual checkpoint and bidders TTI with IO, single agent IO, what is your question? Speaker 4 Haiti, before you start off, I'm so sorry to interrupt you. Speaker 3 But. Speaker 4 Before we dive into the Denoue metastatic, what if the patient has been on pembro now, has progressed or disease has occurred shortly after immunotherapy has subsided and we start there? Speaker 2 Yeah, absolutely. I think that's a really important question that these patients are unfortunately starting. We're starting to see these patients in practice. First of all, I think this is a data free zone where we haven't designed yet a clinical trial that will exactly answer this. I get my data from two sources. One is US understanding how long the immunotherapy kind of combined and blocked T cell or that CD1 engagement. The other context is from some of our studies in refractory RCC settings such as contact O3 and Teeny Vote. For example, they've been on timber Lismab for months. You feel like they've been on it for a period of time that they would have seen the benefit from it and then they start to progress. Then I switch mechanisms of action because in that setting based on contract O3 and T, we have not seen a benefit to adding a switching agency. Patient hasn't really been on IO the first three months and or maybe there were small nodules to start and minimal growth. I might give them the benefit of the doubt and add in probably a TKI at that point. Also similarly, if it's a patient who's been on and now we're more than four months and that's a very again, arbitrary number. But understanding that PD one agent is likely engaged for at least about six months after and that's based on full blood work from patients with Melanoma, then I would say maybe if it's after six months they're starting to progress, I would be a challenge with. Speaker 3 In giving some moving immunotherapy in adjuvant settings, we saw that with genophytes for or periop space for almost all the disease sites. You've seen that with Niagara trial coming our way in bladder cancer. We do this for breast cancer and lung cancer, which is an ongoing issue. It's not black and white. There's a lot of Gray area here. If I have your permission now, can we focus on the NUVO RCC? How to choose a frontline regimen for NSCLC As a good. Speaker 3 Portion of our patients will have the Novo metastatic disease. Katie, you're a signal paradigm here. Speaker 2 Yeah. So, you know, a couple years ago the NCC and guidelines started to change. How would you choose your frontline regimen that was based on IMDC categorization? Now I'll actually bring it back full circle and say now I feel like in the last year given updated data from C1C 2LA for the Binivo. I still use IMDC to give a prognostication to the patient, but I don't necessarily choose my frontline regimen based on IMDC alone. My algorithm is I'll go through and say, OK, well, what is the characteristics of this patient tonight? I do still use IMDC so that if a patient looks like they have poor risk, disease, multiple risk factors, pretend a poor biology is informative to me and helps me advise the patient on prognostications. What it comes down to for me is, is this patient and some type of visceral crisis or such a high burden of disease and pain, for example, from Bony meds that I really don't have an opportunity to rescue with a TKI in the second line space. And so if that's the case, then I will absolutely choose from one of the three great IOTKI regimens that are approved in Frontline 40 to 50% of my patients to Novo metastatic disease. They're often presenting because they have pain from their cancer. And so I think that's probably the percentage of patients that I would be treating with an IOTI. And then for the other, I will, I would like the data that came about just in the last year, which was the eight-year survival data and what it showed us and what was maybe new this year sites just continued durability from that PD1 and CTLA 4 agents for the first time in this data, the intention to treat population had been the intermediate and poor risk they allowed all patients to enroll on trial. So in this year's data they did show that there again, there's a subset of patients with good risk IMDC criteria, kidney cancer patients who had a durable beneficial and often those are the patients who are not needing a response. Maybe patients with small lung nodules who you've been observing for a while and you have that opportunity to try APD 1 and CPLA 4 agent. If you unfortunately don't get benefit, you would still have time to proceed with Quench and CPI. So that's that's why I say I cannot feel like it's come full circle. While we were, you know, initially stratifying our treatments really based on IMDC, now I feel like we need a biomarker. But right now I'm using patient symptoms to help drive my first side. Speaker 4 Thanks for covering that, Katie. Lot to unpack here where we have as you stated, dual checkpoint inhibitor approved. Dual checkpoint inhibitors, immunotherapy with TKI, and liver cancer Along with. Speaker 4 TKI single agent, also immunotherapy with TKI, though the reliance on single agent TKI is rather low. Here we tend to use dual checkpoint or IO plus TKI. Now as you stated for bone or particularly liver, is there one particular one that you we rely on IO plus PKI? Speaker 2 Yeah. These trials shown updated data, chick mate non ER being the NEVO plus Cabo data that was shown, updated just a few weeks ago and continues to show that benefit even in these hard to treat areas like bone and liver. And I think similarly we have seen that from the CLEAR trial, which was the tubroluzumab and lembatinib treatments. So those are the more broader Tkis compared to epsitneb, which is really a pure VEG as targeted. If we're looking at those treatment areas for patients, I often will go either to have Boniva or Pimbro Linda. Speaker 3 Can I push a little more on the same idea out in the community? Would you prefer us sticking with one combination of TKI and IO or be more fluid Saying in this particular scenario, be it more bone Max I tend to share with this or liver disease or early disease. What is your go to preferred agent? Speaker 2 I think it depends on what you're comfortable with. Ultimately, the most efficacious drug in the patient that you're comfortable managing that your team has experience with, that's going to be your best chance for with us. We've seen multiple times, even in the last year that treatment dosage matters. And so I think if you're comfortably because and I have so much respect and I, I want to say that here, I love being a sub specialist and treating just by Gu patients, even in GUI find it so challenging to keep up with everything. So, so much respect for you all who are having to treat so many different diseases, so many different approvals. And that's why I say be comfortable have the one that you like and get in that most those efficacious drug dose does matter starting out at the drug trial started out and then being able to help either do a dose holder a dose reduction as necessary gives the best. Speaker 3 Yeah. And again, Katie, you also brought up those things, which is different when we're using single agent versus when we're using combinations. We have that in mind. We took the side effects. I promise we'll come back to the side effects and some clinical pearls around Tkis and even our second and third line available options before that, if the disease was, then we have data from Tinivo 2. Sequencing TKIs and other agents We have other Tkis available, we have Belsotifan. Katie, how are you sequencing these agents and what data did you have here? Speaker 2 Yeah. So I really want to hit and highlight on, we now have two large randomized phase threes that has shown that if a patient is progressing just off of or recently from point inhibitor that there's no benefit in continuing inhibitor. You know, I think we all want that to be the case because we know that's really the only chance for a durable benefit for the most part. We just saw increased city, increased side effects. If a patient's progressing on that line treatment, then I do sequence KIS and then my choice of sequencing KIS and Bell Zuto Fan. It's a little bit, I think we don't have the right answer. We don't have a sequencing trial to know for sure. Often it's dependent on what you've done in the frontline settings. If you've done Nevo Cabo or Pembre Limba, then I frequently will just reverse and do the opposite in that second line setting. We know of course Bill Zuto Fan and Tavosna both great agents been approved in the 3rd and 4th line setting. Both are either in trials or have just come. So we see data being used earlier in lines of therapy. So I think it's possible that Belzutofan will start to to move earlier. And I know that we've seen some data from Ozna from Teeny Vote showed it's benefits showing a median TFs in this life thing around nine months. So again, I think it's what are you comfortable with? What did you use in the frontline setting? Belzutifan is a newer agent on the market. So if I have just a second, I might touch on that. Great because it's a different side effect profile and gives patients have breaks from hypertension, diarrhea syndrome, all these things that they deal with. Sequencing through TKI is the couple pearls that I have having several patients on the Belzutifen trials and now in senior practice is monitored closely for that anemia that's an on target side effect. When you block hip, you block EPO and it can happen pretty quickly. So I bring them back in every couple weeks in the first several months. Recommendations are to hold or do a dose reduction as needed for the anemia. I even consider using EPO as well and then the other Pearl that I'll is it can result in hypoxia. The percentage they saw in clinical trials was quite low, but with my patients both on trial and in standard practice is it can sneak up on them. Told my patients to take an oximeter and monitor it daily because we can catch it earlier that way. It's quickly is. It's not like it just happens overnight. It's kind of a slow progression, but if they're waiting three weeks or four weeks in between clinic visits, you'd rather catch them earlier than them becoming inside clinic. Speaker 3 That also dose dependence the hypoxia issue here. Speaker 2 So yes, we've, I've had some attempts to hold the drug to get resolution of the hypoxia. You send them home with supplemental oxygen and this side effect resolves. I have been able to dose reduce and not 'cause the hypoxia. I've I've also had the opposite happen where we've dose reduced and still the hypoxia has returned. I think it is just that kind of close monitoring and we still don't really quite understand. There's some hypothesis that it's the effect on the carotid body, multiple comorbidities, COPD and sleep apnea, but I don't think we quite understand who are the individuals who give. Speaker 4 Thanks for covering that, Katie, with regards to Bozoom fan, clinical pros, but with regards to also have any insights that you might have there? Clinical Pros of Bozoomfen The first insight is that from Teen EVO 2 and the combination arm, they used a lower dose due to some concerns by the regulatory agent versus the full dose. We saw the full dose patients treated on full dose, the better PFS and really no differences and quality of life metrics or AE profile. My first Pearl is I would start at the full dose and then down as needed. It's a three-week on one week off regimen similar to prior Sutent. The benefit in that week take off some of the side effects improving. I think just typical TKI monitoring hypertension, we'll see what that pure VEGF effect probably the I see. Speaker 3 And again, Roy, you had brought up that we're using EP Nebo and Melanoma lung cancer. TKI is another thing not to Vosnet. We've used land, tabo and so many other things via ACC, of course, here as well. OK, I know Roy is eyeing the clock. Last question before we close, Katie, any roles NGS in SCC out of clinical trials? Speaker 2 No, Right now I think what NGS can do is give you a sense of the aggressiveness of the disease, but there's no actionable mutations that we typically see. If you did NGS and saw a VHL only, you would say this is maybe a slower growing. If you saw a VHL and a BAP, one mutation you'd use as more aggressive disease. But again, unfortunately currently they're not actionable. And I want to emphasize Belzutifan does not require any testing because 90% of patients have AVHL alteration. Even if it's not an NGS mutation that can be found, they have some type of hypermethylation or something else disrupting that VHL pathway. I get a lot of questions about that. You know, do we need to have of testing or VHL NGS? The answer is no. It's just so commonly altered in clear cell biology that we would just be able to use it without a biomarker in non clear cell. We think because it's not driven by a VHL pathway, we don't typically rely on those in those non cell situations. Speaker 4 Perfect. Hot topic. CCDNAT, DL1 and Ng has no role of that, particularly in kidney space. Though as you stated, CD1 could use NGS for seeing the prognosis aspect, which is tied to VHL. Thank you. Thanks so much for breaking this down for all of us and covering the current treatment paranoid for RCC for our listeners. Conclusion Let's go on a quick recap. Speaker 1 Today with doctor Katie Beckerman from Tennessee Oncology, we have covered RCC from top to bottom in early stage. Pembrolizumab is currently approved in adjuvant setting based off of oral survival benefit in Keynote 564 study. In metastatic space, we have options of epinebo multiple Tkis with immunotherapy or Tkis alone. What would you want to add here? Speaker 3 Yeah, at the first line treatment, if the disease was to progress, we discussed sequencing Tkis that are not used upfront. We also talked about balsutifan for refractory disease, but it is crucial to keep in mind its potential side effects. Anemia and shortness of breath are associated with balsutifan, so that should be on your radar. If you've enjoyed this discussion, be sure to check out our other episodes in Algorithm series covering bladder cancer, prostate cancer, and breast cancer. Our goal is always to support you in the community, so we would love to hear from you. Leave us a review to let us know how this is helping you and how we can continue to do Better Together. Let's bridge the gap between academia and community so that all our patients get the best care close to home. We are the oncology brothers.