Frontline mRCC: I-O/TKI Treatment Regimens

Sumanta Kumar Pal, MD: Dave, I'm going to round out this conversation with you. You told us about your thoughts of nivolumab-ipilimumab. If you had to choose a TKI [tyrosine kinase inhibitors] -I/O [immuno-oncology] regimen, what would it be based on the data you've seen today?

David F. McDermott, MD: Based on my experience—which is admittedly limited with lenvatinib and I have more experience with cabozantinib—and the data that we have now, I would probably still stick with nivolumab-cabozantinib over lenvatinib-pembrolizumab right now. That is in part because I'm more comfortable managing the adverse effect profile. When you reduce the dose of cabozantinib, you make it a lot easier to tolerate.

One distinguishing characteristic between CLEAR—not that you should compare across trials—and CheckMate 9ER is the discontinuation rate of 1 or both of the drugs. It's twice as high in the CLEAR study than it is in nivolumab-cabozantinib. You should make that comparison carefully. We talked earlier about that potentially being impactful on patients. A number of times, you need to stop 1 or both drugs. It seems much less when you lower the dose of cabozantinib than when you give a higher dose of lenvatinib, but I don't have a ton of experience. I wish we had more data on single-agent lenvatinib. That would help educate these discussions more, because that probably is a pretty potent VEGF drug on its own. We just don't have a lot of data on it. That's also a potential drawback of making comparisons across trials, whereas the cabozantinib data package is more robust as a single agent.

Of all of these agents, in combination, axitinib is the easiest for me to manage because it goes away the quickest. If you're talking about which doublet is easiest from a clinician’s point of view, axitinib-pembrolizumab is the easiest. If you have someone with diarrhea, you stop the axitinib. If they’re better a day later, it's the axitinib; if not, you consider steroids or something like that. The problem with cabozantinib is the long half-life. Lenvatinib has a half-life issue, too. It's not as great as cabozantinib.

Robert S. Alter, MD: I'm going to feed you the question, but I want to piggyback on yours. There is obviously data that you put out in regard to the dosing of lenvatinib. I would give you the few seconds to talk about that. I was just going to finish off by saying that in patients in practice and not on clinical trial, we are giving much lower doses that would probably be taking them off clinical trials. The importance is if you have patients not on a clinical trial, and you've seen patients derive a benefit from a therapy, whether it's cabozantinib or lenvatinib, there's still this opportunity of maintaining patients on doses where the package insert would say to discontinue the therapy. In the community, we find that we are able to maintain lower doses than package allows us to do and patients still derive a durable therapy. Do you want to talk about your study about the dosing?

Sumanta Kumar Pal, MD: I'd be happy to. It is actually pretty salient to this discussion on frontline treatment. This was an FDA-mandated study looking at 18 mg vs 14 mg of lenvatinib with 5 mg of everolimus. This was a reasonably sized study with 300 patients. It was a noninferiority study with the primary endpoint of response rate and then treatment-emergent adverse events. The bottom line is that lenvatinib at 14 mg was not noninferior to 18 mg, suggesting that 18 mg is the dose that we should be using in the second- and third-line setting. There were lots of dose reductions and treatment emergent adverse events in this study. We have to think about how this applies to frontline therapy, because if we're trying to maintain dose intensity at 20 mg of lenvatinib with pembrolizumab over the course of time, the data from my study suggests that that's not likely to happen. Those doses are going to step down, and probably even more so in a real-world population. I have concerns about the application of lenvatinib and pembrolizumab in the frontline study. Tom, I'll give you the last word here on selection of TKI-I/O regimen.

Thomas E. Hutson, DO, PharmD: When lenvatinib-pembrolizumab becomes commercially available, it will be a strong addition. The data that we have at 27 weeks is greater than we've seen to date in any of the other I/O-TKIs, or even the I/O-I/O when it comes to the efficacy endpoints at that time point. Where I/O-I/O blows everyone away is the durability of response, which is yet to be clear, but getting 17% response rates with lenvatinib-pembrolizumab is pretty phenomenal. It's in 71% CR [complete response]/PR [partial response] rate. It's phenomenal and hard to discount that.

What everyone is saying is that there is not a lot of going into this data of lenvatinib, so there is going to be an experience gap. And if it exists among KOLs [key opinion leaders], it likely exists in the community, too. What's going to matter for uptake of lenvatinib-pembrolizumab is going to be use of the agent. As we have seen over time, as people start using lenvatinib-everolimus, they start realizing how great of a drug it is and how easy it is to use. That same phenomenon is going to have to happen as we think of lenvatinib-pembrolizumab. Tivozanib is another drug that we've all used and has a great role, too. We see benefits with that drug, and yet most people haven't even heard of it. There's going to have to be an uptake and willingness to use the drug.

Sumanta Kumar Pal, MD: I'm a little less dazzled by that 17% CR rate. I'm really worried about some of the differences in patient populations across these phase 3 studies. Brad, I think you're reading my mind. It looks like you're nodding. What am I talking about there?

Bradley A. McGregor, MD: If you look at the populations, these are different phase 3 trials. It's very hard to compare data set to data set. There seems to be a slightly more favorable risk population with lenvatinib-pembrolizumab than the cabozantinib-nivolumab. The cabozantinib-nivolumab group had the highest proportion of patients who did not undergo a cytoreductive nephrectomy. We know from the different trials to date that those patients are associated with worse outcomes. It is very hard to compare. The data for cabozantinib-nivolumab and lenvatinib-pembrolizumab are both really impressive. It's important with whatever regimen you choose to start with the regimen and, as Bob said, use the dose reductions. I was actively putting patients on both trials, and with cabozantinib-nivolumab, you could go down to 20 mg every other day. With lenvatinib-pembrolizumab, you could go down to 8 mg a day; from 20 mg to 18 mg, to 14 mg, to 10 mg, and to 8 mg. There are lots of dose reductions available. With the lenvatinib-pembrolizumab, there are some toxicity concerns. Over 25% had to stop the lenvatinib in that trial vs less than 10% having to stop cabozantinib. There is a clear difference there, and we had to correlate that with the cabozantinib-nivolumab. I am very impressed by the data of both agents. Both of these combinations have some really salient points that, when you're talking with a patient about different options, what they mean to the patient.

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