TKI/IO Comparison: Lenvatinib/Pembrolizumab Versus Cabozantinib/Nivolumab Versus Axitinib/Pembrolizumab

A roundtable discussion, moderated by Monty Pal, MD, of the City of Hope, focused on updates in renal cell carcinoma (RCC), including treatment in both the frontline and adjuvant settings. Dr. Pal was joined by a panel that included Daniel George, MD; Brad McGregor, MD; and Cristina Suárez Rodríguez, MD.

In the next segment of the roundtable series, the panel compares 3 TKI/IO treatment combinations and discusses the pros and cons of each, how patient characteristics determine selection, and more.

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Dr. Pal: We talked about good-risk disease. We talked about intermediate-risk disease and poor-risk disease. Now let’s dissect further the TKI/IO questions. Amongst the 3 options that we use in this category—lenvatinib/pembrolizumab, cabozantinib/nivolumab, axitinib/pembrolizumab—I’d say those are the 3 most prominent options, what are you typically leading on? Dan, maybe I’ll start with you there.

Dr. George: The truth is, I think we’ve got 3 really good options. I don’t feel like, gosh, there’s 1 drug you have to do. I’ve used all 3 of these, and I’ve been satisfied with all 3 of these and how they can work. But they are different.

The cabozantinib option I like because I’m not giving the full dose. I feel like starting at 40 mg, starting closer to a dose they can tolerate longer term. And many of my patients don’t need a dose reduction, but if they do, I still have 2 dose reductions to go to. It gives me that flexibility. I have a lot of experience with that and been very satisfied.

Pembrolizumab/axitinib has been around the longest, and I like that regimen a lot. The flexibility of going to every 6-week dosing with the pembrolizumab is really nice for our patients, particularly those that come a long distance. The axitinib is particularly nice in patients where I’m worried about the reversibility of toxicity, so if they get significant diarrhea or an issue, I can shut that down, and it’s going to get better quicker. It helps me actually differentiate sometimes mechanistically, what might be driving some of those toxicities. That one has some advantages, but it does have a little bit of more up and down pharmacokinetics. Hypertension might be a little bit harder to find that middle ground on. Those are some of the experience I’ve had.

Lenvatinib/pembrolizumab has been the newest regimen out there, and I’ve been particularly impressed with the responsiveness in that regimen. It is a pretty high dose to start with, but I have patients that can tolerate that. It, surprisingly, seems to be better tolerated than our experiences with lenvatinib/everolimus in the very refractory setting. It’s still something that requires close monitoring and management to get that individual dosing right. I think they all have their strengths and weaknesses. I’ve used them all, and I think I individualized those different characteristics of the drugs in choosing which regimen I’m going to use for each patient.

Dr. Pal: Interesting. So you sort of individualize your approach. I tend to be a little bit more dogmatic. I tend to use a lot more cabozantinib/nivolumab in the upfront setting. I’ve really found that approach that you highlighted so beautifully with cabozantinib is a risky maneuver, going from the 60-mg dose that we’re used to using in the salvage setting, decreasing it to 40 mg in the frontline setting.

But it really worked beautifully with hazard ratios for progression-free survival that are comparable to the other frontline trials. Overall survival hazard ratio that’s identical. We do see some quality of life benefit there as well with a regimen as compared to some of the others that we’ve explored in the frontline setting. That tends to be my approach. Brad, tell us about your approach amongst these TKI/IOs.

Dr. McGregor: I agree. I think they’re all great options because it’s really a matter of being comfortable with dosing. I think the key thing where I talk to a patient about whatever TKI/IO combination is we’re going to start at whatever but it’s okay if we dose reduce. I tell them at the very beginning, so they don’t get worried when they come in in 2 weeks and I’m like, “Listen, you’re having side effects, we should reduce that dose.” In the trials, the majority of the patients did dose reduce, and we saw these impressive results. I’m very quick. Even with cabozantinib 40 mg, half of patients reduce the dose, and that’s okay. We’re going to start this dose, if we have to go down, expect that. We start at lenvatinib 20 mg. We’ll see and it’s okay to.

Dr. George: Do you ever start at a lower dose?

Dr. McGregor: I don’t. I think you need to have that initial high-dose intensity. I tell a patients, “Listen, we’re going to start high. We think there’s a benefit of starting at the highest dose that you can tolerate.” We know that if we reduce the dose for toxicity, we’re not going to be compromising efficacy. That was what was done in the trial. Patients do well with that approach.

I worry, if you start low and the patient feels well, they don’t want to go up and maybe they could have tolerated a higher dose and have better response. I start high and I counsel them very early on. It’s okay to dose reduce. To your point, I think the cabozantinib/nivolumab data is appealing, and it starts with that lower dose of cabozantinib, with impressive results. Then we saw at just this meeting that median overall survival now is close to 50 months with extended follow-up, which is impressive. That’s a marked difference from what we saw before. There may be a tail to the curve with some of these TKI/IO combinations with extended follow-up. Nivolumab/ipilimumab was the first to be done, but now hopefully with these TKI/IOs we see those extended follow-ups and it’ll be great.

Dr. Pal: Cristina, what about you amongst these TKI/IO regimens? Can you pick one amongst the 3?

Dr. Suarez: I agree with everything you have said. We have a complicated situation in my country, since we don’t have them available, and all my experience comes from the clinical trials. I have many, many patients in all these clinical trials, and I cannot choose 1 or the other. At the end of the day, they have the same adverse events, but in a different frequency. At the end of the day, you know how to manage; we have been using TKIs for so many years that I’m not afraid about managing the toxicity. I think it’s difficult to choose 1 or the other.

I always start with the complete, full dose, that’s for sure. Because some patients will need the full dose, and if I need to reduce the dose, it’s okay. Going back to the patient that we were talking about before, like symptomatic patients, then I would choose nivolumab/cabozantinib or lenvatinib/pembrolizumab because the progressive disease rate is just 5% instead of 10% with axitinib/pembrolizumab. But apart from that, it’s difficult to choose 1 or the other.

Dr. McGregor: I agree. I mean like the lenvatinib/pembrolizumab, every 6-week dosing of pembrolizumab is pretty nice. When patients have to drive in to Boston and pay however much money they have to pay for parking. They don’t have to do that every 6 weeks once they get on a standard dose. That’s a great benefit to our patients. Starting with that 20 mg of lenvatinib dose, some patients can tolerate really, really well and if they can’t, you just be quick to dose reduce. I think it’s highly effective.

Dr. George: To Monty’s point, if you’re not treating kidney cancer every week, that’s not like the thing you do like us, having a regimen you’re comfortable with, that your nurses are comfortable with and your staff and everything and just kind of sticking with that, you’re not really going to go wrong here either. The message out there is, they’re all reasonable options and good options for your patients, but they do have differences, and if one of these differences really makes a separation for you for that particular patient, great. Otherwise, it’s okay to treat patients the same with what you’re comfortable with.

Dr. Suarez: At the end, I think it’s very important you monitor the patient very, very closely with it at the beginning.

Dr. Pal: Tight monitoring upfront, and hone in on the right dose for the patient.

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Continue on to watch the next roundtable segment.