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Therapy Selection for Patients With Newly Diagnosed mRCC

Insights From: Brian Rini,MD, Cleveland Clinic Main Campus; David F. McDermott, MD, Harvard Cancer Center
Published: Sunday, Dec 02, 2018



Transcript: 

Brian Rini, MD: For me, frontline therapy changed when ipilimumab /nivolumab got approved in the United States in April of this year, 2018. Prior to that, outside of a clinical trial, we would use single-agent TKI [tyrosine kinase inhibitor] therapy, commonly Sutent [sunitinib] or pazopanib. We’d use nivolumab monotherapy as second line therapy and then another TKI.

When ipilimumab/nivolumab was approved, it became our regimen of choice pretty much for all patients. That does include favorable-risk patients where I know sunitinib had better targeted therapy outcomes, such as response rate in PFS [progression free survival]. But the complete response rate is still higher with ipilimumab/nivolumab, and I think it gives patients the best chance of durable response. In our clinic, in my clinic, we tend to use that as the predominant frontline therapy, assuming patients can tolerate it.

I use a VEGF TKI in the frontline setting if I don’t think patients can tolerate ipilimumab/nivolumab, maybe in an older and frailer patient or somebody with autoimmune disease. People for whom I’m worried that with the potential toxicity, they may not have the organ reserve to fight it. I think that’s, at present, only about 10% of patients or so. The other issue is that I think ipilimumab/nivolumab requires some expertise. We have a number of patients who drive quite a distance to see us. Their local oncologist may or may not be comfortable giving ipilimumab/nivolumab. Usually with those patients, however, I’ll have them get the 4 induction doses with us and then go back to their local oncologist for maintenance. That generally works well.

I don’t, at present, factor risk status much into the decision. I think a lot of people will take their intermediate-/poor-risk patients and give them ipilimumab/nivolumab. In favorable-risk patients, they’ll give a TKI. As I mentioned, I don’t do that. I think ipilimumab/nivolumab is appropriate for favorable-risk patients, but not everybody feels that way. There are datasets coming out now with a VEGF agent plus an immune agent. You can imagine those kinds of combinations might cover the favorable-risk patients and also produce high response rates, and so I think some of this discussion around favorable-risk patients and ipilimumab/nivolumab is going to go away over time because we’ll have other immune-based combinations that are applicable.

PD-L1 is a biomarker and has sort of a long and checkered history in many diseases, including kidney cancer. I would say, in summary, it’s associated with response and it enriches for response, but it’s by no means a perfect biomarker because PD-L1–negative patients can still respond, including complete responses. While it has been looked at in trials and used as a stratification factor, and some trials have used that population for their primary endpoint, I don’t think that in clinical practice at present, until there are more data, it’s terribly useful.

Cabozantinib is unique in that it inhibits MET and AXL, which are receptors that are felt to be important from preclinical models and resistant to VEGF therapy. Cabozantinib was first approved in VEGF-refractory patients, somewhat based on that rationale. It’s clearly an active drug. I think that biochemical profile is what differentiates it. MET and AXL are apparently involved in resistance to VEGF-targeted therapy. This has been shown in several preclinical models. If you target them simultaneously with VEGF therapy, the theory is that you won’t become resistant to VEGF therapy as soon. Technically, it should produce a longer progression-free survival or have activity in VEGF-refractory patients.

Cabozantinib had an interesting development history. The phase I trial was done just in intermediate-/poor-risk patients; I’m not exactly sure why. Then the phase III METEOR trial, which was in the refractory setting, was done with all-comers. And then CABOSUN, which was the frontline randomize phase II trial against Sutent [sunitinib] was done just in the intermediate-/poor-risk population. It’s not really clear to me whether it has enhanced activity in intermediate-/poor-risk patients, as we clearly see with ipilimumab/nivolumab. I think it has more to do with how it was developed. I’m not aware of data that intermediate- or poor-risk patients express MET or AXL more or are somehow more susceptible to cabozantinib. I think it has more to do just with its clinical development plan.

Transcript Edited for Clarity 
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Transcript: 

Brian Rini, MD: For me, frontline therapy changed when ipilimumab /nivolumab got approved in the United States in April of this year, 2018. Prior to that, outside of a clinical trial, we would use single-agent TKI [tyrosine kinase inhibitor] therapy, commonly Sutent [sunitinib] or pazopanib. We’d use nivolumab monotherapy as second line therapy and then another TKI.

When ipilimumab/nivolumab was approved, it became our regimen of choice pretty much for all patients. That does include favorable-risk patients where I know sunitinib had better targeted therapy outcomes, such as response rate in PFS [progression free survival]. But the complete response rate is still higher with ipilimumab/nivolumab, and I think it gives patients the best chance of durable response. In our clinic, in my clinic, we tend to use that as the predominant frontline therapy, assuming patients can tolerate it.

I use a VEGF TKI in the frontline setting if I don’t think patients can tolerate ipilimumab/nivolumab, maybe in an older and frailer patient or somebody with autoimmune disease. People for whom I’m worried that with the potential toxicity, they may not have the organ reserve to fight it. I think that’s, at present, only about 10% of patients or so. The other issue is that I think ipilimumab/nivolumab requires some expertise. We have a number of patients who drive quite a distance to see us. Their local oncologist may or may not be comfortable giving ipilimumab/nivolumab. Usually with those patients, however, I’ll have them get the 4 induction doses with us and then go back to their local oncologist for maintenance. That generally works well.

I don’t, at present, factor risk status much into the decision. I think a lot of people will take their intermediate-/poor-risk patients and give them ipilimumab/nivolumab. In favorable-risk patients, they’ll give a TKI. As I mentioned, I don’t do that. I think ipilimumab/nivolumab is appropriate for favorable-risk patients, but not everybody feels that way. There are datasets coming out now with a VEGF agent plus an immune agent. You can imagine those kinds of combinations might cover the favorable-risk patients and also produce high response rates, and so I think some of this discussion around favorable-risk patients and ipilimumab/nivolumab is going to go away over time because we’ll have other immune-based combinations that are applicable.

PD-L1 is a biomarker and has sort of a long and checkered history in many diseases, including kidney cancer. I would say, in summary, it’s associated with response and it enriches for response, but it’s by no means a perfect biomarker because PD-L1–negative patients can still respond, including complete responses. While it has been looked at in trials and used as a stratification factor, and some trials have used that population for their primary endpoint, I don’t think that in clinical practice at present, until there are more data, it’s terribly useful.

Cabozantinib is unique in that it inhibits MET and AXL, which are receptors that are felt to be important from preclinical models and resistant to VEGF therapy. Cabozantinib was first approved in VEGF-refractory patients, somewhat based on that rationale. It’s clearly an active drug. I think that biochemical profile is what differentiates it. MET and AXL are apparently involved in resistance to VEGF-targeted therapy. This has been shown in several preclinical models. If you target them simultaneously with VEGF therapy, the theory is that you won’t become resistant to VEGF therapy as soon. Technically, it should produce a longer progression-free survival or have activity in VEGF-refractory patients.

Cabozantinib had an interesting development history. The phase I trial was done just in intermediate-/poor-risk patients; I’m not exactly sure why. Then the phase III METEOR trial, which was in the refractory setting, was done with all-comers. And then CABOSUN, which was the frontline randomize phase II trial against Sutent [sunitinib] was done just in the intermediate-/poor-risk population. It’s not really clear to me whether it has enhanced activity in intermediate-/poor-risk patients, as we clearly see with ipilimumab/nivolumab. I think it has more to do with how it was developed. I’m not aware of data that intermediate- or poor-risk patients express MET or AXL more or are somehow more susceptible to cabozantinib. I think it has more to do just with its clinical development plan.

Transcript Edited for Clarity 
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