Perspectives on Metastatic Kidney Cancer - Episode 13
Transcript:Daniel Heng, MD, MPH, FRCPC: Alright. There are other new agents to discuss as well. Paul, I think you were involved in the early work for lenvatinib. Can you talk to us about that?
Paul Nathan, MBBS, PhD, FRCP: I was involved with the phase I study with lenvatinib. It’s a multi-targeted kinase inhibitor. It hits all the appropriate VEGF receptors and PDGF receptors. It also hits KIT and RET. And in this small three-arm randomized study, lenvatinib was looked at versus everolimus as a single agent and also in combination with everolimus. What one can see is that the combination with everolimus is tolerable. And both, lenvatinib, on its own as a single agent, and lenvatinib, in combination with everolimus was superior to everolimus on its own. So there are larger studies planned, or in progress, and we’ll see what folds out of it. I guess the one concern I have is that we keep on making the same mistake; that we tend to do trials where we compare two drugs against one drug, and therefore, when they’re positive we adopt combinations. And what we don’t do is test two drugs against the sequence of both of the individual components. We’ve got data showing it’s active in RECORD-1 after multiple TKIs. It may well be that patients have the same progression-free survival (PFS) benefit from using these drugs in sequence as they do from having the drugs in combination. So, when you look at that small phase II three-arm study and do a little bit of math on the additive PFSs, actually, and there’s no reason to think that everolimus isn’t going to be active after another TKI. We don’t know.
Daniel Heng, MD, MPH, FRCPC: That’s a very good point.
Carlos H. Barrios, MD: That’s true, but that’s exactly the point we were raising before, that recording and registering the treatment beyond progression and trying to stabilize that scientific analysis of this. It’s obviously extremely important for that kind of analysis and that will remain with the question.
Nizar M. Tannir, MD, FACP: The difference, Paul, is in the lenvatinib plus everolimus trial, the median OS with the combination was 25 months.
Susanne Osanto, MD, PhD: It was impressive.
Nizar M. Tannir, MD, FACP: That is impressive, similar to nivolumab.
Susanne Osanto, MD, PhD: And the doses were reduced for most of the drugs.
Paul Nathan, MBBS, PhD, FRCP: But it’s a small phase II randomized study. In fact, it was so small that, the combination wasn’t statistically superior to single agent lenvatinib, even though the numbers were ..... So that’s the point. So how many small studies have we seen that turn into ....
Carlos H. Barrios, MD: We need the phase III data.
Nizar M. Tannir, MD, FACP: I think the important thing about this trial is this is the first trial that combined a VEGFR TKI plus an mTOR inhibitor, and was deliverable. And we all know about all the other trials where a VEGF plus an mTOR inhibitor was toxic and did not show any advantage in terms of efficacy — PFS, response rate, certainly not OS. I don’t know what’s unique about this lenvatinib, but it seems like it is combinable with an mTOR inhibitor, it produced a 43% response rate, a PFS in the 14- or 15-month range, and a 25-month median OS. I think it’s impressive. We’ll wait and see. I don’t think the FDA is going to approve it in an area that’s already competitive and we have so many drugs.
Paul Nathan, MBBS, PhD, FRCP: But it is possible that patients could get just as much benefit if they had lenvatinib first, everolimus second, and have less toxicity all the way through.
Nizar M. Tannir, MD, FACP: It’s a good point. The only thing is I see if this regimen, the combination, is approved, it’s a life line or a life jacket for everolimus because we were talking about everolimus being pushed down the ladder to the bottom. And I think if this combination is an approved, it will have its own space. It’s a life line for everolimus.
Transcript Edited for Clarity