Choosing an IO/TKI Doublet for RCC Patients: Efficacy Data, Dosing, and More

By Brian Rini, MD, FASCO - Last Updated: March 10, 2023

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.

Dr. Rini: Let’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’t really talk about those. Let’s go in reverse; Moshe, and start with you. Let’s take ipilimumab/nivolumab off the table. You’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’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’m also comfortable dropping the TKI and knowing that the toxicities with axitinib’s short half-life will resolve relatively quickly.

Dr. Rini: That’s just an eyeball test.

Dr. Ornstein: There’s no fancy test for it. I tell my patients that in 2023, still the best test we have is the eyeball test. There’s no MRI that’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’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’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’m sure we’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’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’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’ve get gotten really comfortable using the cabozantinib/nivolumab drugs. I’ve seen with the 40-mg dose, especially if you’re using it upfront, I’m not struggling a lot with toxicities. Of course, any patient who you start on TKI, even if it’s 5 mg of axitinib, you’re going to have some toxicities, but in my practice, I’m seeing that this combination is really well tolerated. I’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’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’s what I’ve seen in my practice too. I’ve picked my choice. I’m using a lot of cabozantinib/nivolumab just because I’m comfortable managing the toxicities related to the combination. I’m comfortable with the data, and that’s just been my practice.

Dr. Rini: Very reasonable. Monty, I think I might know what you’re answer is going to be.

Dr. Pal: I’m glad you’re sitting down because this is going to be shocking. I tend to mirror Shuchi’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’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’ve tried with lenvatinib. We’ve done the dose-finding studies with it and haven’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’t talk about it, but all the OS hazard ratios are almost identical, which is really surprising. They’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’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’m seeing in my surrounding community, I just don’t know that the patient is getting the intended advantage from the CLEAR study. I think that’s really significantly common.

Dr. Ornstein: I tend to think, and I tell this to patients and when I’m discussing with others, I do believe that there’s something about the lenvatinib 20 mg dose. I say, if you’re worried that your patient won’t be able to tolerate lenvatinib 20 mg, give a different regimen. But I also agree with what you were saying, that I don’t know what the marginal benefit, if you could say there really is one between lenvatinib/pembrolizumab and cabozantinib/nivolumab. If I’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’t have a ton of experience in the community setting and you’re comfortable with 1 regimen, then just give it well.

Dr. Rini: It’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’s give as much as possible. I’m sure there are people who get cabozantinib/nivolumab or axitinib/pembrolizumab who are underdosed for TKI; I’m sure of it. It obviously didn’t affect the survival advantage for either, but conversely, there’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’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’s a bit all over the map.

Continue on to watch the next roundtable segment.

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