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CABOSUN Trial of Upfront Cabozantinib in Metastatic RCC

Panelists: Robert A. Figlin, MD, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center; Eric Jonasch, MD, University of Texas MD Anderson Cancer Center; Toni K. Choueiri, MD, Dana-Farber Cancer Institute; Michael R. Harrison, MD, Duke Cancer Institute; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published Online: Tuesday, Apr 18, 2017



Transcript:

Robert A. Figlin, MD:
Toni, I want to revisit something you talked about. I want to push you for both positive aspects of the observation as well as the challenges of the observation. There’s a trial that Alliance has done called CABOSUN. The argument is that we really don’t have much in the way of upfront comparative data other than the old COMPARZ trial, which was Votrient (pazopanib) compared with sunitinib. Then, here comes along a next-generation TKI called cabozantinib that has activity against other targets, AXL and MET, and we recognize that 1 mechanism, or a mechanism of VEGF resistance, is upregulation of MET. So, they went head-to-head, they compared cabozantinib to sunitinib, and the sunitinib that they gave was traditional sunitinib, 4/2. I would suggest that many of us don’t do 4/2 very much anymore when we’re giving sunitinib, although that is the dosing schedule that is FDA approved and serves as the control arm for many, many studies. Secondly, it was an investigator-assessed response trial, so there was not central review, and their endpoints were the traditional endpoints. So, for our audience, let’s review the goal of the CABOSUN data, the limitations of the CABOSUN data, and what you think you would need to know if the CABOSUN data resulted in a different TKI as an upfront treatment for metastatic kidney cancer.

Toni K. Choueiri, MD: Great question, Bob. So, just to remind you about the CABOSUN data, this is a randomized phase II trial of 157 patients that compared the standard sunitinib and the regular 4/2 schedule—which is the schedule that all the ongoing and planned randomized phase III trials in the first-line setting are still using in the absence of non-retrospective data—with cabozantinib, which is another next-generation, I don’t know if they call it second or third now, TKI. It’s a drug that targeted the VEGF receptor but also MET and AXL. Investigator assessment response was the primary endpoint and was met, 8.2 months versus 5.6 months. And a lot with Cooperative Group was limited; I would say funding investigator-assessed PFS and response was accepted. In a lot of situations, we go back and we do an independent review like we’re going to do with CABOSUN. Interestingly enough, the thing that doesn’t need a central review is the overall survival. The overall survival was not going in the wrong direction. Everything, even at the median follow-up of 20 or more months—which is short on this trial—the overall survival, at least numerically, favored cabozantinib. And the side effect profile is another thing that you don’t need central review for and that were equivalent. So, I think these data, despite being randomized phase II, are extremely exciting, and hopefully it will get more exciting when there is a central review and when there is more follow-up for survival.

Now, it does fit. This is a drug that was superior to everolimus in the second-line setting. It’s not a first-comer drug that out of nowhere was tested against sunitinib. This is a drug that has data in the second-line, has very strong data post sunitinib, PFS up to 9 months, and has significant preclinical work—a lot from Eric’s lab that showed that really MET and AXL in xenograft developed resistance to sunitinib—that could reverse that resistance. So, the whole story is there, but I do agree with you. It’s 1 trial, it’s randomized phase II, and there will be central review on survival, like what happened with the lenvatinib/everolimus study. It was initially reported as investigator-assessed and then later on, the independent review happened and the data did hold.

Robert A. Figlin, MD: So, I think, David, that summary by Toni puts us on alert for what may be a paradigm shift in what’s available in the frontline setting with respect to TKIs.

Transcript Edited for Clarity

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Transcript:

Robert A. Figlin, MD:
Toni, I want to revisit something you talked about. I want to push you for both positive aspects of the observation as well as the challenges of the observation. There’s a trial that Alliance has done called CABOSUN. The argument is that we really don’t have much in the way of upfront comparative data other than the old COMPARZ trial, which was Votrient (pazopanib) compared with sunitinib. Then, here comes along a next-generation TKI called cabozantinib that has activity against other targets, AXL and MET, and we recognize that 1 mechanism, or a mechanism of VEGF resistance, is upregulation of MET. So, they went head-to-head, they compared cabozantinib to sunitinib, and the sunitinib that they gave was traditional sunitinib, 4/2. I would suggest that many of us don’t do 4/2 very much anymore when we’re giving sunitinib, although that is the dosing schedule that is FDA approved and serves as the control arm for many, many studies. Secondly, it was an investigator-assessed response trial, so there was not central review, and their endpoints were the traditional endpoints. So, for our audience, let’s review the goal of the CABOSUN data, the limitations of the CABOSUN data, and what you think you would need to know if the CABOSUN data resulted in a different TKI as an upfront treatment for metastatic kidney cancer.

Toni K. Choueiri, MD: Great question, Bob. So, just to remind you about the CABOSUN data, this is a randomized phase II trial of 157 patients that compared the standard sunitinib and the regular 4/2 schedule—which is the schedule that all the ongoing and planned randomized phase III trials in the first-line setting are still using in the absence of non-retrospective data—with cabozantinib, which is another next-generation, I don’t know if they call it second or third now, TKI. It’s a drug that targeted the VEGF receptor but also MET and AXL. Investigator assessment response was the primary endpoint and was met, 8.2 months versus 5.6 months. And a lot with Cooperative Group was limited; I would say funding investigator-assessed PFS and response was accepted. In a lot of situations, we go back and we do an independent review like we’re going to do with CABOSUN. Interestingly enough, the thing that doesn’t need a central review is the overall survival. The overall survival was not going in the wrong direction. Everything, even at the median follow-up of 20 or more months—which is short on this trial—the overall survival, at least numerically, favored cabozantinib. And the side effect profile is another thing that you don’t need central review for and that were equivalent. So, I think these data, despite being randomized phase II, are extremely exciting, and hopefully it will get more exciting when there is a central review and when there is more follow-up for survival.

Now, it does fit. This is a drug that was superior to everolimus in the second-line setting. It’s not a first-comer drug that out of nowhere was tested against sunitinib. This is a drug that has data in the second-line, has very strong data post sunitinib, PFS up to 9 months, and has significant preclinical work—a lot from Eric’s lab that showed that really MET and AXL in xenograft developed resistance to sunitinib—that could reverse that resistance. So, the whole story is there, but I do agree with you. It’s 1 trial, it’s randomized phase II, and there will be central review on survival, like what happened with the lenvatinib/everolimus study. It was initially reported as investigator-assessed and then later on, the independent review happened and the data did hold.

Robert A. Figlin, MD: So, I think, David, that summary by Toni puts us on alert for what may be a paradigm shift in what’s available in the frontline setting with respect to TKIs.

Transcript Edited for Clarity
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