The Role of Lenvatinib in Advanced RCC
Robert A. Figlin, MD: Tom, we have this dilemma. We have a randomized phase II trial of everolimus versus lenvatinib versus the combination demonstrating a clear improvement in progression-free survival, with some adverse-event profiles that suggests that you have to pay a price for that extension in progression-free survival. But, we also have an FDA approval of this agent in combination. So, talk a little bit about the data set, the positives, and the challenges, and help the community doctor know when this might be a reasonable alternative.
Thomas Hutson, DO, PharmD: I was blessed to be part of the development plan for the lenvatinib/everolimus combination. And that was a phase II trial that was recently reported this past year and subsequently led to approval for Lenvima, the brand name of lenvatinib, in early May. That trial was designed for the refractory patient population. They were essentially second-line patients with clear cell histology, predominantly. And lenvatinib was interesting. The biologic rationale for lenvatinib is that it’s an FGF (fibroblast growth factor) inhibitor, and FGF may be an angiogenic escape mechanism. We have tried FGF inhibitors in the past, and they have not really proved to be fruitful. But, this particular drug also combines VEGF inhibition, which was quite strong. And so, there was rationale to take that agent and combine it with an agent with a different mechanism of action: an mTOR inhibitor. But, we do believe, I would hope that mTOR still has a role to play; we just haven’t really figured out that patient population. But combining a VEGF inhibitor with this potential FGF blockade, which may be an escape mechanism, with an mTOR inhibitor was the trial. This was the first combination that has shown to be beneficial of the modern TKI combination studies. In fact, this is the only one. The bevacizumab/interferon was a different breed of a combination strategy.
The results were quite stunning. I participated on the trial, put the patients on the trial, and they seemed to tolerate it. So, despite what appears to be excess toxicity, when I compare the toxicity profile of this drug and lay it next to the toxicity profiles of METEOR and CheckMate-025—with all the nuances of reporting, all-cause toxicity versus treatment-related toxicity that the different drugs have been reported as having—I see just slight differences in toxicity in the patients. And I can tell you that my patients on trial were able to be managed, as you would expect. Most of the toxicities we saw were class-effect toxicities with mTOR inhibitors and VEGF inhibitors. Patients did require dose reductions, and the lenvatinib dose between 14 mg and 18 mg, with 5 mg of everolimus, seemed to be a more practical dose that most people would tolerate.
We talked about a trifecta. There was a trifecta with this agent. There was a response rate benefit. There was a PFS benefit of the combination of 14.6 months, I believe. And then the response rate benefit was, in independent review, almost 30%. With investigator assessment, it was in the 40th percentile range, and an overall survival benefit was observed as a second opinion. I think the downside has already been brought out, that it’s a randomized phase II trial. And so, there’s some skepticism, maybe rightfully placed, about how does one interpret this in that setting. For myself, as someone who put patients on the trial, I found it to be an active…I’ve had a patient on the trial, that was a spokesperson patient for the drug who had failed two VEGF inhibitors and immunotherapy, that received this combination therapy and had a response.
So, clearly, I think we’ve all seen that there are drugs that work in patients, and this adds to that. Where we sequence it is going to be a challenge, and I think it’s a welcome addition. But now it’s going to be, how do we actually sequence that? And I think we’re going to want to give our patients that—which has been brought up already by Dr. Tannir when he talked about everolimus—that this drug would be naturally combined. Any time you want to use everolimus, you’re going to want to use this combination for sure. That, in my mind, lands itself as a fourth-line position. The question is, where do we use axitinib then if you’re using this now fourth-line?
Nizar M. Tannir, MD: First-line, axitinib first-line in combination.
Thomas Hutson, DO, PharmD: Okay, there we go. That has been solved.
Nizar M. Tannir, MD: That’s the lifeline for axitinib.
Thomas Hutson, DO, PharmD: So, clearly there’s going to be a role for it. The question is going to be, how will the data mature? We’re presenting a poster at this meeting with updated results. How do we sequence? Does it have a role earlier, second or third? And we’ll just have to see.
Robert A. Figlin, MD: Dan?
Daniel J. George, MD: Yes. I just want to make one comment, too, because I think there’s something unique about this combination. When we looked at combinations of everolimus with sunitinib, it was not well tolerated at all. We saw new toxicities, hemolytic-uremic syndromes, and major cytopenias that were just not tolerable even in the first cycle. There’s something different about this combination that makes it tolerable in a multi-center prospective study like this. So, I think we have to recognize that. I wouldn’t go trying to extrapolate these data into other TKIs plus everolimus. And then, we have had some studies where we’ve looked at bevacizumab and everolimus in combination. There we have seen some increased toxicity, but we didn’t get the efficacy. There is something to this combination, I think it needs to be studied more. We need to understand it more, but this is different from what we’ve seen in the past when we’ve tried to combine agents with everolimus.
Robert A. Figlin, MD: Tom?
Thomas Hutson, DO, PharmD: Just a final thought there. The drug was approved, Lenvima. It already has a regulatory approval for thyroid cancer. It received this label extension and a new indication in kidney cancer as a full approval. And so, there will be a postmarketing commitment for a trial, but they don’t need to repeat this trial as a phase III. The actual plans, which will hopefully be made public soon, will be to study this earlier in the disease course. It’s a phase III trial, and likely a frontline setting.
Transcript Edited for Clarity