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The Role of Lenvatinib and Cabozantinib in RCC

Panelists:Robert A. Figlin, MD, Cedars-Sinai Medical Center; Sandy Srinivas, MD, Stanford University Medical Center; Nizar M. Tannir, MD, FACP, MD Anderson Cancer Center; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Apr 04, 2016


Transcript:

Robert A. Figlin, MD:
Sandy, it would be easy for us if this was the end of the story. But it’s not the end of the story and there’s two additional pieces of information that are just around the corner that are going to complicate these even further. So let’s spend some time talking about some as yet unapproved but recently studied and presented data on both the role of lenvatinib and the role of cabozantinib. Let’s first talk about lenvatinib. So Bob Motzer reported, at ASCO, a randomized trial comparing the combination of lenvatinib and everolimus compared with a control. And it was a randomized trial, and the results were striking, striking so much that maybe the FDA will consider that sufficient information for their approval; that’s in their domain. But tell us a little bit about this drug called lenvatinib, what it does, why it might be doing something differently than other VEGF-receptor TKIs, and should we maybe keep our minds open about combination therapy in the second-line setting.

Sandy Srinivas, MD: Exactly. I think we spoke about combinations before, but this might be opening the combination therapy story all over again. So lenvatinib targets VEGF, but it also targets FGF, and that’s always been thought as a mechanism of resistance. So this was a three-arm trial, and they looked at lenvatinib as a single agent compared to everolimus as a single agent, but also used a lower dose of both lenvatinib and everolimus. And what really surprised me was that the PFS for the combination was almost double that of single-agent lenvatinib. And the PFS for everolimus was similar to what we have seen in its original approval. So I think that the patient population is real, so seeing everolimus with a PFS around 5 months makes you think that that’s real. But the combination resulted in a PFS of almost 14 months, which was really astonishing.

I think it is real, and the side-effect profile was not that different from what you expect for VEGF and mTOR inhibitor. But it’s hard to get too excited about combinations. I don’t know if people would go back to it. Would you get the same if you were to do it sequentially? And I don’t know how people would feel about taking two drugs. Both are oral, unlike the other combinations that we have spoken about in the past.

Robert A. Figlin, MD: But we have a 13- or 14-month PFS in the second-line setting, which is far superior to any other agent that’s been used in that setting. And Nizar, let’s talk about cabozantinib and the METEOR study because here we have an agent that is different. I’d like you to describe what it does and some of the results of that New England Journal article, and then maybe as a group, we can then have a conversation, imagining that these agents might be commercially available sometime for us in the future. How are we going to navigate through this decision making?

Nizar M. Tannir, MD, FACP: Sure. I think you know cabozantinib is interesting because, in addition to the VEGF receptors, as we mentioned, it blocks c-MET and AXL. And we published a paper from our group in Oncogene a few months ago looking to support this clinical trial, although the trial METEOR was designed and launched, and conducted, before the results of our preclinical work. But our preclinical work suggested that tumors that are treated with sunitinib do have an escape mechanism with AXL and C-MET Bringing along a drug that blocks this does actually produce tumor growth inhibition. I think now we finally believe that the c-MET and the AXL pathways are pathways that are relevant in progression, certainly after VEGF exposure.

The METEOR trial was a large phase III trial looking at 658 patients randomized between cabozantinib and everolimus. The primary endpoint was progression-free survival and astonishingly, it showed 7.4 months of median PFS with cabozantinib compared to 3.8 months median PFS with everolimus. And there was a trend for the secondary endpoint, overall survival, also in favor of cabozantinib. So I anticipate this drug to be approved pretty soon, so it will be number 10 for us in our armamentarium, to have for our patients.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Robert A. Figlin, MD:
Sandy, it would be easy for us if this was the end of the story. But it’s not the end of the story and there’s two additional pieces of information that are just around the corner that are going to complicate these even further. So let’s spend some time talking about some as yet unapproved but recently studied and presented data on both the role of lenvatinib and the role of cabozantinib. Let’s first talk about lenvatinib. So Bob Motzer reported, at ASCO, a randomized trial comparing the combination of lenvatinib and everolimus compared with a control. And it was a randomized trial, and the results were striking, striking so much that maybe the FDA will consider that sufficient information for their approval; that’s in their domain. But tell us a little bit about this drug called lenvatinib, what it does, why it might be doing something differently than other VEGF-receptor TKIs, and should we maybe keep our minds open about combination therapy in the second-line setting.

Sandy Srinivas, MD: Exactly. I think we spoke about combinations before, but this might be opening the combination therapy story all over again. So lenvatinib targets VEGF, but it also targets FGF, and that’s always been thought as a mechanism of resistance. So this was a three-arm trial, and they looked at lenvatinib as a single agent compared to everolimus as a single agent, but also used a lower dose of both lenvatinib and everolimus. And what really surprised me was that the PFS for the combination was almost double that of single-agent lenvatinib. And the PFS for everolimus was similar to what we have seen in its original approval. So I think that the patient population is real, so seeing everolimus with a PFS around 5 months makes you think that that’s real. But the combination resulted in a PFS of almost 14 months, which was really astonishing.

I think it is real, and the side-effect profile was not that different from what you expect for VEGF and mTOR inhibitor. But it’s hard to get too excited about combinations. I don’t know if people would go back to it. Would you get the same if you were to do it sequentially? And I don’t know how people would feel about taking two drugs. Both are oral, unlike the other combinations that we have spoken about in the past.

Robert A. Figlin, MD: But we have a 13- or 14-month PFS in the second-line setting, which is far superior to any other agent that’s been used in that setting. And Nizar, let’s talk about cabozantinib and the METEOR study because here we have an agent that is different. I’d like you to describe what it does and some of the results of that New England Journal article, and then maybe as a group, we can then have a conversation, imagining that these agents might be commercially available sometime for us in the future. How are we going to navigate through this decision making?

Nizar M. Tannir, MD, FACP: Sure. I think you know cabozantinib is interesting because, in addition to the VEGF receptors, as we mentioned, it blocks c-MET and AXL. And we published a paper from our group in Oncogene a few months ago looking to support this clinical trial, although the trial METEOR was designed and launched, and conducted, before the results of our preclinical work. But our preclinical work suggested that tumors that are treated with sunitinib do have an escape mechanism with AXL and C-MET Bringing along a drug that blocks this does actually produce tumor growth inhibition. I think now we finally believe that the c-MET and the AXL pathways are pathways that are relevant in progression, certainly after VEGF exposure.

The METEOR trial was a large phase III trial looking at 658 patients randomized between cabozantinib and everolimus. The primary endpoint was progression-free survival and astonishingly, it showed 7.4 months of median PFS with cabozantinib compared to 3.8 months median PFS with everolimus. And there was a trend for the secondary endpoint, overall survival, also in favor of cabozantinib. So I anticipate this drug to be approved pretty soon, so it will be number 10 for us in our armamentarium, to have for our patients.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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