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Trial Data on Cabozantinib in Renal Cell Carcinoma

Panelists:Carlos H. Barrios, MD, PUCRS School of Medicine; Daniel HEng, MD, MPH, FRCPC, Tom Baker Cancer Center; Paul Nathan, MBBS, PhD, FRCP, Mount Vernon Cancer Centre; Susanne Osanto, MD, PhD, Leiden University Medical Center; Nizar M. Tannir, MD, FACP, University of Texas MD Anderson Center
Published: Monday, Apr 11, 2016


Transcript:

Daniel Heng, MD, MPH, FRCPC:
So now we also have another therapy, cabozantinib, which is a VEGF, MET, and AXL inhibitor. Nizar, do you want to talk about the top-line results of the METEOR study?

Nizar M. Tannir, MD, FACP: Sure. So the METEOR trial was a phase III trial that looked at recruiting patients with clear cell RCC after a VEGFR TKI. The eligibility criteria were very liberal. They allowed any number of prior VEGFR TKIs, as long as the patients had progression within six months of enrolling on trial. And the comparator for cabozantinib was everolimus, similar to the CheckMate 025 study we discussed just a minute ago. Everolimus was the comparator. Unlike the CheckMate 025 study, the primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), and response rate, and safety, etc. The impressive results with cabozantinib were that the median PFS with cabozantinib was 7.4 months compared to 3.8 months median PFS with everolimus. So that was statistically significant. Response rate was also 21% versus 5%, similar to the response rate in the CheckMate 025 study. We are awaiting the OS data. It has not matured yet. I think in early 2016 we will have the data, but there was a trend seen.

Daniel Heng, MD, MPH, FRCPC: A strong trend.

Nizar M. Tannir, MD, FACP: A strong trend favoring cabozantinib over everolimus in terms of the secondary endpoint, OS. So actually it’s a VEGFR TKI plus a c-Met inhibitor plus an AXL inhibitor. We were talking about resistance earlier in the discussion. So this agent is novel in the sense that it’s targeting two pathways that are considered to be upregulated in VEGFR-treated patients, so the c-Met pathway and the AXL pathway. And I think it is very possible that the reason cabozantinib was so effective in this salvage setting after the VEGFR TKI is because it’s targeting the c-Met and the AXL pathways. So, obviously, now this brings us another therapy that will be hopefully approved soon for our patients. It’s another drug to treat our patients within the salvage setting.

Daniel Heng, MD, MPH, FRCPC: It’s great to have all that choice. Paul, how do you cope with all that choice? We have axitinib, everolimus, cabozantinib, and nivolumab.

Carlos H. Barrios, MD: He has only two lines.

Susanne Osanto, MD, PhD: NICE! Nice for you.

Daniel Heng, MD, MPH, FRCPC: We need funding.

Paul Nathan, MBBS, PhD, FRCP: Remember, the thing about NICE approval is that when they say it’s approved, actually the companies don’t need to market the drugs very heavily in the UK because there’s an expectation that there’s a standard of care and there’s equal access across the country. And, actually, I think that’s been really important in terms of raising the bar about the quality of care. And we don’t have this problem with community oncologists doing strange things as happens in many other places around the world. So there are lots of benefits, if the drug is approved. We’ll see obviously. Assuming cabozantinib and nivolumab are improved, the first implication is that the role of everolimus gets pushed further down the treatment algorithm. I think we’re yet to see which patients in whom we should be using targeted therapies as a preference versus which patients we should be using immunotherapy. We don’t know that yet.

There are forthcoming subset analyses planned on the CheckMate 025 data which may start to tease out some of the story. My preference generally has always been that if one is trying to use immunotherapy to get durable responses, and you know that you’ve got targeted agents that are active when somebody is progressing, there is a logic in using immunotherapy earlier rather than later. Of course, we don’t have data set in that setting yet. There are ongoing trials not least the combination ipilimumab/nivolumab study. But, at the moment, I’m assuming we’ll have nivolumab access and cabozantinib access. And my preference probably will be to try to get the immunotherapy in earlier rather than later, but that’s a prejudice rather than being data driven.

Daniel Heng, MD, MPH, FRCPC: Carlos, what’s your impression? Is there any difference between IV versus PO treatment or tolerability with either? How would you choose in the second line now that we have all this data?

Carlos H. Barrios, MD: Certainly the IV mode of administration is one of the things that obviously impacts the way we select therapy. But I think the efficacy still remains the most important thing, controlling the disease for the longest period of time. I was impressed with the results of the METEOR study in the sense that it almost doubled the PFS. It’s the first time we go over this three, four, or five months so that’s very impressive. I would eagerly await the survival data because I guess the critical issue here is how to choose the second-line immunotherapy versus the second-line anti-VEGF, -MET TKI. So that’s an interesting question— I think we’re going to have to challenge that. To tell you the truth, I don’t know. I think we need the clinical data. We need to run the trial in order to see what happens and we need to collect biological information in order to analyze what happens to the tumor to see if we can tease out who are the patients that may benefit from one of the two approaches. At this point, we don’t have either agent available in Brazil, so that makes it very easy. I just say, well clinical trials are the right answer.

Nizar M. Tannir, MD, FACP: You don’t even have axitinib approved in Brazil.

Carlos H. Barrios, MD: We don’t even have axitinib.

Nizar M. Tannir, MD, FACP: So, for you, it’s a VEGFR TKI followed by everolimus.

Carlos H. Barrios, MD: Everolimus, that’s all we have. We have a lot of clinical trials at our center specifically. We just finished recruiting on the combination, ipilimumab/nivolumab trial versus sunitinib, which was very interesting and generated a lot of interest in the patient community, and with the doctors as well, because it makes the potential for improving on the response rates and maybe even in the long-term survival—PFS and survival data in that regard like happened in the melanoma arena. So, the point being that we need to collect this information in order to inform our future research.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Daniel Heng, MD, MPH, FRCPC:
So now we also have another therapy, cabozantinib, which is a VEGF, MET, and AXL inhibitor. Nizar, do you want to talk about the top-line results of the METEOR study?

Nizar M. Tannir, MD, FACP: Sure. So the METEOR trial was a phase III trial that looked at recruiting patients with clear cell RCC after a VEGFR TKI. The eligibility criteria were very liberal. They allowed any number of prior VEGFR TKIs, as long as the patients had progression within six months of enrolling on trial. And the comparator for cabozantinib was everolimus, similar to the CheckMate 025 study we discussed just a minute ago. Everolimus was the comparator. Unlike the CheckMate 025 study, the primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), and response rate, and safety, etc. The impressive results with cabozantinib were that the median PFS with cabozantinib was 7.4 months compared to 3.8 months median PFS with everolimus. So that was statistically significant. Response rate was also 21% versus 5%, similar to the response rate in the CheckMate 025 study. We are awaiting the OS data. It has not matured yet. I think in early 2016 we will have the data, but there was a trend seen.

Daniel Heng, MD, MPH, FRCPC: A strong trend.

Nizar M. Tannir, MD, FACP: A strong trend favoring cabozantinib over everolimus in terms of the secondary endpoint, OS. So actually it’s a VEGFR TKI plus a c-Met inhibitor plus an AXL inhibitor. We were talking about resistance earlier in the discussion. So this agent is novel in the sense that it’s targeting two pathways that are considered to be upregulated in VEGFR-treated patients, so the c-Met pathway and the AXL pathway. And I think it is very possible that the reason cabozantinib was so effective in this salvage setting after the VEGFR TKI is because it’s targeting the c-Met and the AXL pathways. So, obviously, now this brings us another therapy that will be hopefully approved soon for our patients. It’s another drug to treat our patients within the salvage setting.

Daniel Heng, MD, MPH, FRCPC: It’s great to have all that choice. Paul, how do you cope with all that choice? We have axitinib, everolimus, cabozantinib, and nivolumab.

Carlos H. Barrios, MD: He has only two lines.

Susanne Osanto, MD, PhD: NICE! Nice for you.

Daniel Heng, MD, MPH, FRCPC: We need funding.

Paul Nathan, MBBS, PhD, FRCP: Remember, the thing about NICE approval is that when they say it’s approved, actually the companies don’t need to market the drugs very heavily in the UK because there’s an expectation that there’s a standard of care and there’s equal access across the country. And, actually, I think that’s been really important in terms of raising the bar about the quality of care. And we don’t have this problem with community oncologists doing strange things as happens in many other places around the world. So there are lots of benefits, if the drug is approved. We’ll see obviously. Assuming cabozantinib and nivolumab are improved, the first implication is that the role of everolimus gets pushed further down the treatment algorithm. I think we’re yet to see which patients in whom we should be using targeted therapies as a preference versus which patients we should be using immunotherapy. We don’t know that yet.

There are forthcoming subset analyses planned on the CheckMate 025 data which may start to tease out some of the story. My preference generally has always been that if one is trying to use immunotherapy to get durable responses, and you know that you’ve got targeted agents that are active when somebody is progressing, there is a logic in using immunotherapy earlier rather than later. Of course, we don’t have data set in that setting yet. There are ongoing trials not least the combination ipilimumab/nivolumab study. But, at the moment, I’m assuming we’ll have nivolumab access and cabozantinib access. And my preference probably will be to try to get the immunotherapy in earlier rather than later, but that’s a prejudice rather than being data driven.

Daniel Heng, MD, MPH, FRCPC: Carlos, what’s your impression? Is there any difference between IV versus PO treatment or tolerability with either? How would you choose in the second line now that we have all this data?

Carlos H. Barrios, MD: Certainly the IV mode of administration is one of the things that obviously impacts the way we select therapy. But I think the efficacy still remains the most important thing, controlling the disease for the longest period of time. I was impressed with the results of the METEOR study in the sense that it almost doubled the PFS. It’s the first time we go over this three, four, or five months so that’s very impressive. I would eagerly await the survival data because I guess the critical issue here is how to choose the second-line immunotherapy versus the second-line anti-VEGF, -MET TKI. So that’s an interesting question— I think we’re going to have to challenge that. To tell you the truth, I don’t know. I think we need the clinical data. We need to run the trial in order to see what happens and we need to collect biological information in order to analyze what happens to the tumor to see if we can tease out who are the patients that may benefit from one of the two approaches. At this point, we don’t have either agent available in Brazil, so that makes it very easy. I just say, well clinical trials are the right answer.

Nizar M. Tannir, MD, FACP: You don’t even have axitinib approved in Brazil.

Carlos H. Barrios, MD: We don’t even have axitinib.

Nizar M. Tannir, MD, FACP: So, for you, it’s a VEGFR TKI followed by everolimus.

Carlos H. Barrios, MD: Everolimus, that’s all we have. We have a lot of clinical trials at our center specifically. We just finished recruiting on the combination, ipilimumab/nivolumab trial versus sunitinib, which was very interesting and generated a lot of interest in the patient community, and with the doctors as well, because it makes the potential for improving on the response rates and maybe even in the long-term survival—PFS and survival data in that regard like happened in the melanoma arena. So, the point being that we need to collect this information in order to inform our future research.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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