Managing Toxicities of TKIs and HIF-2 inhibitor in Renal Cell Carcinoma (RCC)

Navigating Starting Doses for Frontline TKI Therapies Hello everyone and welcome back to another episode of the Oncology Brothers Podcast. I'm Rahul Ghosain, as always, I'm here with my brother and Co host Rohit Ghosain. We're back for another toxic episode where we're not only talking about the shifting landscape in cancer, but the focus here is rather on the agents that are already approved and how to manage their side effects better. It's not only about living with cancer, but we have to keep the quality of life at the center of all this for our patients. Today, we're diving into oral treatment options, particularly the tyrosine kindness inhibitors and HIF 2 inhibitor that we use in treating renal cell carcinoma. For this, we're excited to be joined by a world renowned medical oncologist, Dr. Monty Paul from the City of Hope. Monty, thank you for joining us. Speaker 2 Thanks so much and thanks for all the great work you 2. You guys are amazing. Speaker 3 We continue to learn from folks like yourself. So thanks so much for joining us, Monte. Over the next few minutes, let's focus on Tkis and HIF 2A inhibitor, what we have available for our renal cell carcinoma disease. I'm hoping this will help us get more comfortable in managing some of the toxicities tied with these drugs without compromising quality of life. We are covering quite a few agents here, but we'll soon learn that there is a class effect associated with them as opposed to single agent side effect profile. We'll start with the frontline options with immunotherapy, tabozantinib, lenvatinib and then diving into pezoponib and sunitinib, which doesn't get utilized that often and then closing off with the second line agents, that is belzutifan and tivozinib. Monty, can we start with excetinib, linvatinib and cabozantinib? Starting dose with excetinib is 5 milligrams and then uptight rating and down tight rating based on tolerability aspect Tizen. And then cabozantinib 40 milligrams with nivolumab versus 60 milligrams when used as a single agent and we tend to utilize 40 milligrams. Lastly, not the least, but linvatinib 20 milligrams with immunotherapy, 18 milligrams with everolimus. In your practice, how do you go about starting the dose here? Speaker 2 Yeah, absolutely. You know, I will say that the way you have it broken down here is perfect, right? You have the mechanism of action laid out and that really does sort of explain the spectrum of toxicity. So you know, it's something like exitinib where you really have sort of a potent and specific VEGF inhibitor, right? You end up getting a lot of hypertension, you know, maybe a little bit less of some of the day-to-day toxicities of diarrhea and hand foot syndrome. I've always found the titration of exitinib to be a little bit wieldy. And the reason I say that is that, you know, it's a pretty well established paradigm to start at 5 milligrams twice daily and reduce the dose if toxicity is incurred. I find that uptight trading is always a challenge, right? You start a patient on a drug, they're comfortable kind of right. So I rent a very few cases where I can actually up try trade to 7 and 10 milligrams. Candidly cabazatinib is probably the most common TKI that I use. Being a multi kinase inhibitor, you might expect a bit more in the way of perhaps hand foot syndrome, diarrhea and so forth and association with it. It's an interesting point you make around 40 versus 60 milligrams. Totally agree. If you're going to do Cabo nivo, you got to start with 40 milligrams, just as the label suggests. As far as the monotherapy indication, let's say you're using it second or third line or maybe up front for a patient with contraindications to immunotherapy. I always try to start at 60, right? Because you never know. I mean, I've had these tiny, frail little ladies who do amazing with cabozantin. I just can't predict who's going to be the one incurring toxicity. My big burly football players, oftentimes they'll struggle with that 60 milligram dose. I do meet with the patient frequently during that first month or two and encourage dose reduction. I do the same thing with levatinib. With levatinib, I start with 20 milligrams or 18 milligrams depending on the scenario we're using it in. And I tell that patient, I have no expectation that you're going to maintain this dose. Rarely am I able to do that. I always tell them call us if you're having toxicity and don't try to be a hero. Stop the drug dose reduce as needed. Balancing TKI Efficacy with Unique and Overlapping Toxicities And again, the reason why we're focused on the dose here is because these side effects are often dose dependent hypertension, diarrhea, those hand foot syndrome, we run into Monty, any clinical pearls around managing these common side effects? Speaker 2 You know, the one thing that I will say is that although there may be a temptation to start at a lower dose, I do get a little bit worried at what that means for a patient in terms of getting clinical benefit. I'll give you an example. I ran a clinical trial to randomize phase two, but it's actually the largest experience that we have to date prospectively was lenvatiniboneverolamus and it was a comparison of 14 versus 18 milligrams of vivatin paired with 5 milligrams of ever illness. You would think that based on dose reduction starting at 14 milligrams, you would have leaps and bounds better tolerability. That wasn't the case. The tox profile is pretty similar, but there really was a decrement clinical benefit. So I would caution the listener from trying to dose reduce, but still extrapolating the same clinical benefit downstream. Just as you point out, Rahul, there's definitely a dose response relationship. So if you're going to take down that dose, the patient has to be aware that you're going to compromise efficacy to some. Speaker 3 Extent and thanks so much for adding that Monty, because we see the patients and as a clinician we always worry about that is the efficacy tied in when we are to dose reduced and as you stated for Linvatnab that is the case. Would you consider same thing for carbozantinib and exetnib as well? Speaker 2 You know, the dose response relationship exists across most drugs. Tom Hudson gave us beautiful talk that did show dose response relationships between, for instance, synitinib increasing doses did not show a dose relationship with desopinib. It's not consistent across all drugs. But my clinical observation and the observation from prospective studies now like the one I cited with lenvatinib is that if you reduce the dose, you're going to get less of a response. Speaker 1 As community oncologists, we're also seeing breast cancer and lung cancer. We have long term data where we're decreasing the dose because of the side effects and thankfully we're not compromising their outcomes. Monty, coming back to RCC, when we're talking about side effects, some of these side effects can also overlap with immunotherapy. How do you tell what is the underlying cause in that particular situation? Speaker 3 Especially symptoms like diarrhea. Speaker 2 So I'll just kind of dovetail on Rohit's example of diarrhea. I think the best thing to do if you've got a TKIIO combination is a perfect example of that overlapping talks. I would stop the TKI. You know, you really have to keep in mind the half life of the drug, you know, for tamizant of about four days for accident, much shorter, you know, a couple of hours in those particular settings. You wait for the TKI to wash out. If the diarrhea is still there, you know it's the immunotherapy that's the culprit and you can start treating accordingly with steroids for whatever's indicated. Speaker 1 And when we're talking about exeptinib, carbazanantinib, limbatinib, are there any unique side effects to one or the other or still we're sticking with the class effect here, Monty? Speaker 2 Yeah, yeah. So just building on this very nice slide that you have here with these themes of mechanistically what they're doing right, you know, exitinib being more potent specific and focused on VEGFR 1, hypertension, probably greater signal with that drug. With cabazan that may be more in the way of diarrhea and hand foot syndrome with lenvatinib, fatigue and diarrhea really tend to be dose limiting in my experience. The colitis is real, you know, and so I think patients need to be aware that when they're using lenvatinib, and I believe this really applies across settings, whether it's a pad cellular and a metriol, that colitis is something that needs to be guarded against to the greatest possible. I think that we need to advise patients not to let the diarrhea get to extremes when they're on that that drug, call their provider and talk about dose reduction. Speaker 1 And Rohit, we see this cabozantinib is also approved now for neuroendocrine tumor and we're struggling saying is it the disease or the treatment that's causing this colitis? So a few things to keep in mind. Optimizing Tivozanib Dosing and Holiday Strategies for RCC OK, now switching gears to the two other Tkis, which are not commonly used because we have better options. Sanitinib and pizzopinib both have black box warning of hepatotoxicity. But again, hypertension, diarrhea, severe fatigue are big concerns. Monty, your thoughts? Speaker 2 Yeah, I agree with you. They're a little bit antiquated these days, but we still have our legacy patients who remain on these drugs after years. My suggestion is the considerations here are no different than with cabazatinib or levatinib. If you hit substantial amounts of diarrhea etcetera, try to dose reduce. I'm actually surprised whenever I talked to colleagues in the community at the experiences, they have the positive experiences using bizopinib and it's actually a very well tolerated drug by many. You do have to be warned, as you point out very aptly brought well about the pad of toxicity, but otherwise a reasonable treatment option that I sometimes pull out in the salvage setting for that patient who's really kind of due for 6th or 7th or 8th line therapy. Speaker 3 Now in contrast to sunitinib and pasopinib, what we have in second line treatment is tivozinib and belzutifan, which is HIF 2A inhibitor. Let's start off with tivozinib, which is still a TKI, the only TKI with some data we have after we have exhausted IO, but importantly better tolerated when compared to other Tkis. Monty, your what's here? Speaker 2 I totally agree with your assessment. If I'm looking at tavaasinib juxtaposing against the other options, mechanistically it seems more similar to axitinib. I find it to be better tolerated than axitinib in many regards. You know, even less in the way of hand foot syndrome, even less in the way of diarrhea. You know, hypertension with this drug, just like with axitinib is real, needs to be guarded against. One of the reasons I have such great respect for my community based colleagues is my gosh, there's so many complicated dosing strategies to remember. How can you ever remember 1.34kg and .89 milligrams? Those are the 2 starting dose and stepwise dose reductions and respectively. And the other thing I'll point out because by community based colleagues is that it's three weeks on and one week off. 1 little Pearl that I've employed in practice is that, you know, that seven day holiday, just like we used to do with Snitnit for instance, is something that you can toy around with a little bit. I've had some patients who say by the time I get to day 18 out of the 21 prescribed days, I feel like I need to stop. My advice to them is to stop, have a longer holiday and utilize that to recuperate from side effects so they can get back on to the next cycle of therapy. I find that patients really love that holiday approach. Speaker 1 Monty, can we take another minute to talk more about those? Again, this is second line. Our patients have had progressive disease. They're more fatigued, exhausted, though this is better tolerated. We have two doses, 1.34kg or with teenivo 2 study, 0.89 milligrams was used upfront. In your clinical practice, do you start at 1.34kg or is there a patient where you rely on starting at .89 and then maybe up titrating? Speaker 2 It's a great question. I would still start with that 1.34 milligram dose and I've been doing this for 20 years. I'm just blown away at how little I know about, you know what, which patients are going to derive toxicity from drugs, right? So, you know, I'm always surprised at how well people can do on 1.34 milligrams. It really is a very well tolerated drug. Then I'll step down to .89 milligrams as needed. It's a little tricky because you're right, 1.34 milligrams is the starting dose of the drug. Three weeks on, one week off. You can go down to .89 milligrams afterwards, but that doesn't suit the patient. After that, you can actually go to .89 milligrams every other day as opposed to the three-week on, one week off dosing strategy that's in the label. So, you know, especially because this isn't probably a drug one's going to use every day, it's worth consulting with the label just to kind of work through that dose titration schedule. Speaker 1 Monty, before we run away from Triviazonab, when you are running into side effects, is there more that you're going to take that extra week off or decrease the dose? Speaker 2 I try to start by giving more time with any of these drugs. I kind of try to do some back of the napkin math. For instance, I'm calculating for it. Let me use cabazanum as an example, right? You know, sitting down with one of my patients yesterday in clinic and she was on a 40 milligram dose of drug, right? And I said to her, we'll take a couple of holidays during the course of the month here and there, right? And she said, well, you know, is that safe? And I said the alternative for us is to step down to 20 milligrams. She said no, no, no, no, no, don't want to do that, right? Do that. Back to the napkin math, right? And if a patient is taking the equivalent of 20 milligrams a day, if they're taking more than half of that month off, step down the dose. But what I try to emphasize to patients is if they're taking weekends off from their therapy with cabazatinib, they're still getting more than they would with a dose reduction of the drug. So we try to do that math in the clinics. And I find that it's a good mechanism to convey to patients what the relative merits are of dose reduction versus maintaining the dose with breaks. I find that oftentimes because they feel more comfortable if you're able to convey to them that, hey, look, you know, you're taking a couple of days off, but you're still getting way more drug than you would in a cumulative fashion than stepping down the dose entirely. Speaker 1 And again, as community oncologist, we're doing this coming back to that breast cancer example where some of the medications are three weeks on, one week off or myeloma patients that are on Revlimid, 3 weeks on, one week off. And we see this over and over. The patients absolutely appreciate that week off from the medication. Speaker 3 Sometimes patients would rather hideaway the side effects when you introduce the topic of dose reduction, but they will be more open if you are to just take a break. But we'll still keep on the same dose that's. Speaker 2 True, I totally agree with you. There's a really interesting psychology around it. I think it's probably one of the most important conversations we have is Medox. Speaker 3 Indeed, quality of life has to be the center of these conversations and patient shared decision making is very important. Managing Hypoxia and Anemia with Belzutifan in RCC Now before we close, let's touch on an outlier here in terms of mechanism faction that is Belzutifan, a HIF to alpha inhibitor. With this we have to worry about dyspnea and hypoxia. Why is this even more important? Because patients feel the effect significantly. Another side effect tied is anemia. Monty, any clinical pearls and managing side effects? Yeah. Speaker 2 Well, you know, I think it's great the way that you have this position here because this really is the choice right 2025 that clinicians have. Is it to positive? I know we're talking about toxicity here, but if I may riff for a second on efficacy, you know, a couple of notes. Although I think has an excellent tolerability profile by and large relative to perhaps TK eyes, I will say that I've been a little bit underwhelmed by the performance of the drug in terms of progression free survival response rate. And in the pivotal trial that led to the approval of Bell Zootifan Lightspark OO5, it's hard to sort of responses are quite slow and latent to the drug, right? So when you talk about patients in the salvage setting where you need a response or at least need stabilization quickly, you may not get it from the strategy. That being said, if you have a patient who just can't tolerate the side effects of Tkis, it's reasonable to sequence this earlier. In terms of the main side effects of this TIFF 2 inhibitor, you worry about me and hypoxia. Those two first side effects that you have listed there are spot on. But we're talking about the anemia. It's about 80% of patients are gonna have some degree of anemia. It's about 35 to 40% that are gonna have significant anemia. One thing that I've really struggled with, got more comfortable with over time is the principle of giving growth factors. EPO and other red cell growth factors had a sordid history in oncology. I was really apprehensive at first, but after talking to colleagues, I think the renal cell community in general has sort of adopted the approach of getting comfortable with giving EPO as a means of sort of supplementing the anemia. I think checking iron levels and supplementing with IV iron is absolutely critical as well for this patient population. And of course, if all else fails, dose reduction, right? You're starting at 120, you can go to 80 and then down to 40. I think it's important to consider that if you really do have patients that are hovering at low hemoglobin levels, hypoxia is a little bit more of a struggle. I tell all my patients, buy a pulse oximeter, check your pulse daily, and I give them this magic number of 92%. If you go below 92%, please stop the drug and call us. About 15% of patients are going to have significant hypoxia associated with Belzutafan. In my experience there's nothing you can do but dose reduce and try again. I don't think there's any other method of ameliorating hypoxy. You look for secondary causes. But if you start belzutifan and right away you're seeing deterioration of pulse ox. Unless that patient is rapidly progressing in the lungs I would suspect it's drug induced. Put the drug on hold and try a lower dose. Speaker 3 And in that particular scenario where you have received a call and the patient is say about 85 to 88%, are you going to hold the therapy or rather dose reduce? What are the next steps like evaluation in the hospital to rule out secondary causes because these patients might not have COPD or other secondary causes in those settings? Speaker 2 Yeah, I think that if your clinical intuition is that it's driven by the drug alone, you don't need to drag that patient at the ER for assessment. You know, you can maybe sort of let the patient set off of drug for a couple of days and you know, see if and of course this requires interpretation of whole constellation of symptoms, right. But having said that, I would suggest that again, this is one of those really tricky side effects where all you can do is is dose reduced to ameliorate it. Speaker 1 Absolutely. Again, we've covered a lot here and out in the community. It's not only about keeping up with that new approval, but we have to get comfortable with managing these side effects that come along with our available options. Monty, thank you so much for touching on these clinical pearls and managing side effects for these common options available for RCC for our listeners. Let us go over a quick recap from today's discussion. Speaker 3 Today in our discussion with Doctor Monty Paul, we focused on managing side effects for Tkis and HIF 2A inhibitor commonly used in treating renal cell carcinoma. From options in frontline settings that are often combined with immunotherapy such as cabozetinib, lenvatinib and exetinib to second line treatment options such as tibosnib and belzutifan, we talked through clinical pearls such as dosing, treatment breaks and supportive care management. We have to keep the quality of life in mind when treatment intent is palliative in metastatic settings. Speaker 1 Yes, that is absolutely essential. During our conversation when we were focusing on TK is it was brought up that diarrhea, fatigue and hypertension. It's more of a class effect with almost all of these. TK is though Tibozinib is perhaps one of the better tolerated. TK is here. Besides tyrosine kinase inhibitors, we also touched on bosutifan and the importance of keeping hypoxia and anemia in mind when using this. Speaker 3 We have now done a few of these talks check episodes and we hope that these conversations are making you more comfortable in managing some of the common side effects we see in our day-to-day clinical practice. Thanks for tuning in. Make sure to check out our other discussions around treatment algorithms, conference highlights, and challenging cases from the community. We are the oncology brothers.