Brian Rini, MD, FASCO

GU Oncology Now

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt University Medical Center, focused on the spectrum of therapy for frontline renal cell carcinoma (RCC), including a comparison of monotherapy and doublet and triplet treatment options. Dr. Rini was joined by a panel that included Monty Pal, MD; Moshe Ornstein, MD; and Shuchi Gulati, MD, MSc.In the next segment of the roundtable series, the panel compares 3 treatment regimens: axitinib/pembrolizumab, cabozantinib/nivolumab, and lenvatinib/pembrolizumab.&mdash;Dr. Rini: Let&rsquo;s talk about immuno-oncology (IO)/tyrosine kinase inhibitors (TKIs). It sounds like for 80%-plus of our patients, and I think probably in the US, it is an IO/TKI doublet. There are 3, axitinib/pembrolizumab, cabozantinib/nivolumab, and lenvatinib/pembrolizumab, that have shown a survival advantage. Two others showed progression-free survival (PFS), but not overall survival (OS). We won&rsquo;t really talk about those. Let&rsquo;s go in reverse; Moshe, and start with you. Let&rsquo;s take ipilimumab/nivolumab off the table. You&rsquo;re going to give this patient an IO/TKI. How are you choosing which one? Are you always using the same one? Do you vary based on X, Y and Z?Dr. Ornstein: Yeah, I put my patients into 2 camps within the IO/TKI regimen. It&rsquo;s either an axitinib/pembrolizumab patient or a cabozantinib/nivolumab slash lenvatinib/pembrolizumab patient. Meaning, I find that axitinib/pembrolizumab is easier to tolerate for a patient who is older and might have more comorbidities, where I want to try that doublet. But I&rsquo;m also comfortable dropping the TKI and knowing that the toxicities with axitinib&rsquo;s short half-life will resolve relatively quickly.Dr. Rini: That&rsquo;s just an eyeball test.Dr. Ornstein: There&rsquo;s no fancy test for it. I tell my patients that in 2023, still the best test we have is the eyeball test. There&rsquo;s no MRI that&rsquo;s going to help with that. Then with cabozantinib/nivolumab and lenvatinib/pembrolizumab, I find them a little bit tougher for patients to handle, and I really don&rsquo;t think the toxicities that are seen in the clinical trial setting are necessarily reflected in clinical practice. I find sometimes that we see these numbers and high rates of grade 3 or 4 toxicity. But actually in clinical practice, patients can tolerate these medications a little bit better than in the trial setting.Then within those 2, I generally will favor lenvatinib and pembrolizumab. Now, it&rsquo;s not kosher, as we say, to compare them head to head, but when you look at the numbers, I think if you had taken a group of RCC experts 5 years ago and asked them what they would need to see from a trial to at least make that a preferable regimen, they would say complete response rates at 15% to 20%, PFS close to 2 years, response rates over 70%. Those were the numbers that we saw. Again, it can be a little bit harder to tolerate for some patients because the lenvatinib is at a higher dose, which I&rsquo;m sure we&rsquo;ll get to. But I do think in some ways it set itself apart with those numbers. I will lean primarily on that for the patient who is young and healthy.Dr. Rini: Who are you giving cabozantinib/nivolumab to then?Dr. Ornstein: I generally give much more of the lenvatinib/pembrolizumab. I give cabozantinib/nivolumab probably more in the non-clear cell setting, so if I have a patient with papillary RCC.Dr. Rini: That&rsquo;s fair. We can touch on non-clear cell at the end. Shuchi, what do you think? How do you decide among the 3?Dr. Gulati: I have to agree with everything that Moshe said. There&rsquo;s no head-to-head data to compare these regimens. I was taught as a fellow, pick 1 regimen and get comfortable using it. As it happens, I&rsquo;ve get gotten really comfortable using the cabozantinib/nivolumab drugs. I&rsquo;ve seen with the 40-mg dose, especially if you&rsquo;re using it upfront, I&rsquo;m not struggling a lot with toxicities. Of course, any patient who you start on TKI, even if it&rsquo;s 5 mg of axitinib, you&rsquo;re going to have some toxicities, but in my practice, I&rsquo;m seeing that this combination is really well tolerated. I&rsquo;ve struggled a little bit with lenvatinib, even when we were using it with everolimus in the second-line, third-line, or advanced settings. I tend to prefer the cabozantinib/nivolumab data. We&rsquo;ve seen higher response rates with the lenvatinib, but then there was about more than 30% of patients who had to stop that drug because of grade 3 or above toxicities. Those rates were lower with the other IO/TKIs, and that&rsquo;s what I&rsquo;ve seen in my practice too. I&rsquo;ve picked my choice. I&rsquo;m using a lot of cabozantinib/nivolumab just because I&rsquo;m comfortable managing the toxicities related to the combination. I&rsquo;m comfortable with the data, and that&rsquo;s just been my practice.Dr. Rini: Very reasonable. Monty, I think I might know what you&rsquo;re answer is going to be.Dr. Pal: I&rsquo;m glad you&rsquo;re sitting down because this is going to be shocking. I tend to mirror Shuchi&rsquo;s practice with cabozantinib/nivolumab in the bulk of my patients. I think the dosing strategy to me was a shocker when they announced the CheckMate-9ER study going from 60 mg in the salvage setting down to 40 mg upfront. I thought it was a big risk, but I think it&rsquo;s a risk that paid off in a big way. I found the 40-mg dose to be a lot more tolerable, and especially applied in the frontline setting when you juxtapose that strategy against lenvatinib. We&rsquo;ve tried with lenvatinib. We&rsquo;ve done the dose-finding studies with it and haven&rsquo;t seen that dose adjustments really lend themselves to significantly reducing toxicity. I do find that with cabozantinib, we get away with the same OS advantage with probably less duress from the patient.Dr. Rini: We didn&rsquo;t talk about it, but all the OS hazard ratios are almost identical, which is really surprising. They&rsquo;re all 0.70, 0.71. I tend to be an IO/TKI user. The lenvatinib/pembrolizumab data, to me, is convincing. Like you say, we shouldn&rsquo;t compare, but we have to compare when selecting patients. I think lenvatinib 20 mg is very difficult. I do start at that. When I talk to other oncologists in the community, nobody starts at 20 mg.Dr. Pal: That really worries me, Brian. Because I feel like when folks are starting at lenvatinib 10 mg or 14 mg, which is what I&rsquo;m seeing in my surrounding community, I just don&rsquo;t know that the patient is getting the intended advantage from the CLEAR study. I think that&rsquo;s really significantly common.Dr. Ornstein: I tend to think, and I tell this to patients and when I&rsquo;m discussing with others, I do believe that there&rsquo;s something about the lenvatinib 20 mg dose. I say, if you&rsquo;re worried that your patient won&rsquo;t be able to tolerate lenvatinib 20 mg, give a different regimen. But I also agree with what you were saying, that I don&rsquo;t know what the marginal benefit, if you could say there really is one between lenvatinib/pembrolizumab and cabozantinib/nivolumab. If I&rsquo;m doing these community discussions and they say we give a lot of cabozantinib/nivolumab or even we give a lot of axitinib/pembrolizumab knowing that the hazard ratios are all leveling out right about the same place. If you don&rsquo;t have a ton of experience in the community setting and you&rsquo;re comfortable with 1 regimen, then just give it well.Dr. Rini: It&rsquo;s interesting, the 3 regimens took very different approaches to TKI dosing. Axitinib, start in the middle, go up or down. Cabozantinib was starting kind of in the middle, started a notch down. Lenvatinib was like, let&rsquo;s give as much as possible. I&rsquo;m sure there are people who get cabozantinib/nivolumab or axitinib/pembrolizumab who are underdosed for TKI; I&rsquo;m sure of it. It obviously didn&rsquo;t affect the survival advantage for either, but conversely, there&rsquo;s a lot of patients who are overdosed at lenvatinib 20 mg.I said this last night at a meeting, after 20 years, we still have no idea how to give TKIs. We have no idea how to dose them. We have no idea how to titrate them. I&rsquo;ve thought about this a lot, and we still have no idea, amazingly, 2 decades later. Because you do this, and I do that, and somebody else does that. It&rsquo;s a bit all over the map.&mdash;<a href="https://guoncologynow.com/post/rcc-doublet-considerations-immune-mediated-toxicity-duration-of-treatment-and-more">Continue on to watch the next roundtable segment.</a>