Lenvatinib Plus Pembrolizumab or Everolimus for mRCC

Sumanta Kumar Pal, MD: I'm going to ask a question that alludes to the lenvatinib-everolimus arm rather than the arm that we're maybe going to be focused on, which is lenvatinib-pembrolizumab. Tom, I'm going to direct this to you. This is our first comparison to TKI [tyrosine kinase inhibitor] vs TKI plus mTOR [mechanistic target of rapamycin]. I want to get your thoughts in terms of whether you think lenvatinib everolimus is a regimen that we can use in a frontline setting in some patients.

Thomas E. Hutson, DO, PharmD: I would hope that we could. Lenvatinib everolimus does have some differential activity in non–clear cell, especially the chromophobe. It would be nice to be able to utilize that agent as a frontline indication. It doesn't have that yet. It's a refractory second-line agent based on its FDA approval. This trial showed us that it has a degree of activity that puts it in the ballpark of the other TKI regimens that we utilize in the front line. But how that would carve out and how I would be able to fine-tune the patient population that would justify its approval would be hard for me to say. I don't think there's necessarily a benefit of it across the board outside of that non–clear cell caveat that I mentioned. I would love to be able to use it, but it doesn't add. We have several, so I can't see much of a distinction over, for instance, a cabozantinib front-line approach. There is some crossing of the survival curves that I don't think we're prepared to talk about yet that make people wonder if lenvatinib everolimus is as strong as sunitinib. Is something happening at the tail of the curve there? We have to remember that the data is still 27 months. A small number of patients made it out that far. There are still some issues with post-progression therapy. That's about all I can say about lenvatinib everolimus. I'd love to have it first-line, but don't see that happening.

Sumanta Kumar Pal, MD: I am interested in that phenomenon of the crossover of the curves. This is a perfect opportunity for us to explore that. Dave, Tom, and I have been involved in a study of tivozanib vs sorafenib. The whole reason we're doing that study is the front line PFS [progression-free survival] advantage, but overall survival overlapped here. Looking at the lenvatinib-everolimus front-line data, with that cross in the OS [overall survival] curve, does that mean we should toss it out like we did tivozanib?

Thomas E. Hutson, DO, PharmD: No, I don't think so. Some people bring that up as an issue—that maybe something is going on there that's detrimental—but there are too many other possible explanations for that. I felt the same with tivozanib. I was part of TIVO-1. I feel the same with that regimen, too. I believe Tian had made a brilliant message about wanting to use an agent like lenvatinib-pembrolizumab up front based upon what we see happen clinically—that attrition of patients as we move from first to second-line to third-line therapy. You want to go with your strongest, most potent, and active regimen first because you don't know if someone is going to make it into second or third line therapy. Using something like a lenvatinib-pembrolizumab, which has the greatest data we've seen to date, makes sense in the front line. Tian, I don’t know if I have spoken out of turn for you. Hopefully you agree with that.

Tian Zhang, MD: I appreciate that. I do think for rapid disease control up front, lenvatinib-pembrolizumab makes a lot of sense. If we're thinking about sequencing, I’m not sure how much I will use it in terms of whether we should save it for later lines of treatment. The data from CLEAR are quite promising. I need to use more lenvatinib up front in combination with pembrolizumab to see that toxicity, because when I use it in refractory patients, I see a lot more toxicity and difficulty to manage those toxicities. It's all anecdotal experience in how we will use these combinations. With lenvatinib with everolimus up front, we saw PFS improvement compared with sunitinib and objective responses that were a little higher. The overall survival was not increased. I hate to use doublet therapy with increased adverse events and cost in that setting when I'm not improving survival. CLEAR has certainly pushed immunotherapy doublets into the front line space.

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