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Metastatic RCC: Using Frontline Ipilimumab/Nivolumab

Panelists: Daniel George, MD, Duke Cancer Institute; Neeraj Agarwal, MD, Huntsman Cancer Institute; Robert Alter, MD, Hackensack University Medical Center; Bradley McGregor, MD, Dana-Farber Cancer Institute; Nicholas J. Vogelzang, MD, FASCO, FACP, Comprehensive Cancer Centers of Nevada
Published: Friday, Apr 06, 2018



Transcript: 

Daniel George, MD: I want to switch gears to nivolumab/ipilimumab combinations now, because in renal cell carcinoma, we may have a second tumor where combination use of checkpoint inhibitors becomes another alternative standard of care in the frontline setting. Bob, do you want to tell us a little bit about those data?

Robert Alter, MD: We can go back to what Hans Hammers talked about or presented several years ago, looking at the combination first in utilizing nivolumab and ipilimumab in different doses: using ipilimumab at 3 mg/kg, nivolumab at 1 mg/kg; nivolumab at 3 mg/kg, ipilimumab at 1 mg/kg; and then both at 3 mg/kg. Of course, the patients who got ipilimumab and nivolumab at 3 mg/kg each had to be censored out; 6 patients had different toxicities. But after that, the analysis of the data, with a median follow-up of 22 months, showed the response rate was almost 40% from utilizing that combination of immunotherapy and working by different mechanisms. One is anti–PD-1 and one is anti–CTLA4, but the combination was well tolerated and it actually had significant activity against this tumor. Of course, that was based upon data they had with melanoma and extrapolating moving forward.

Recently presented were the CheckMate-214 data that also saw a significant benefit in patients who received the combination. That was a phase III clinical trial comparing patients with clear-cell renal cell carcinoma in intermediate- and poor-risk patient populations, but they did have favorable-risk patients as well. They looked at sunitinib at the standard dose of 50 mg daily for 4 weeks on, 2 weeks off compared with ipilimumab at 1 mg/kg, nivolumab at 3mg/kg given every 3 weeks for 4 cycles, and continued nivolumab as maintenance therapy.

There was an improvement in all parameters that they were looking for compared with sunitinib in the intermediate- and poor-risk patient populations when it came down to disease-free survival, overall survival, and even some toxicity that seemed to be favoring the combination of immunotherapy as well. There was an issue, of course, when it came down to patients who had favorable risk in that population, where sunitinib seemed to have an improvement in the parameters. But this is the start of a new focus about how we should be considering our patients. It is yet to be FDA approved, but this is how we’re inclined to think now that we’re going to move forward in the next few months.

Nicholas J. Vogelzang, MD, FASCO, FACP: The thing that impressed me with Hammers’ paper that just came out in The Journal of Clinical Oncology is not only the CR rate, which you don’t normally see with sunitinib or a TKI, but also the duration. I think Hans’ paper was published 3 years ago now. Some of these people are still going. That’s impressive. So, I think it’s the new era.

Daniel George, MD: Interesting. Neeraj, at your practice now, you’ve got a lot of experience with TKIs. Is this the new era? Does this change for everybody? How do you integrate this new I-O therapy into the frontline space?

Neeraj Agarwal, MD: As Rob just mentioned, in the favorable-risk category patients, sunitinib outperformed the ipilimumab/nivolumab combination. It was very clear. So, I would not likely consider ipilimumab/nivolumab, the checkpoint inhibitor combination, for favorable-risk patients. I would be very hesitant to do that.

Nicholas J. Vogelzang, MD, FASCO, FACP: That’s only 20% though.

Neeraj Agarwal, MD: Still, I want to start with the risk stratification. So, if you exclude favorable-risk patients, I agree with Dr. Vogelzang. For 80% of patients who definitely belong to poor-risk categories, the ipilimumab/nivolumab combination has shown itself to be superior to sunitinib. And then I start looking at the subgroup analysis, with the caveat that I should not be doing subgroup analysis in a big phase III trial. I feel compelled to do that because I have options, and those options have not been compared with each other and will likely not be compared with each other down the line, at least in the near future.

With those caveats, if I look at the intermediate- and poor-risk patients in the CheckMate trial who did not have PD-L1–expressing tumors, there was really no PFS benefit. Progression-free survival benefit was not there with the ipilimumab/nivolumab combination over sunitinib. On the other hand, if I look at the PD-L1–expressing tumors, defined as more than 1% of PD-L expression, there was a really remarkable PFS benefit: around 22 months with the ipilimumab/nivolumab combination versus 5 months with sunitinib. So, that is something I like to keep in mind.

Secondly, if you look at intent to treat in all intermediate- and poor-risk patients, the PFS benefit was not there if you just combine all of the patients. However, the overall survival benefit was finally presented in the SITC meeting just a few months ago, and it was present in almost all intermediate- and poor-risk patients. But if I look at PD-L1–expressing patients, the overall survival benefit was a lot more remarkable, with a hazard ratio of something in the 0.4 or 0.5 range compared with PD-L1–negative patients, where the hazard ratio was 0.75.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: I want to switch gears to nivolumab/ipilimumab combinations now, because in renal cell carcinoma, we may have a second tumor where combination use of checkpoint inhibitors becomes another alternative standard of care in the frontline setting. Bob, do you want to tell us a little bit about those data?

Robert Alter, MD: We can go back to what Hans Hammers talked about or presented several years ago, looking at the combination first in utilizing nivolumab and ipilimumab in different doses: using ipilimumab at 3 mg/kg, nivolumab at 1 mg/kg; nivolumab at 3 mg/kg, ipilimumab at 1 mg/kg; and then both at 3 mg/kg. Of course, the patients who got ipilimumab and nivolumab at 3 mg/kg each had to be censored out; 6 patients had different toxicities. But after that, the analysis of the data, with a median follow-up of 22 months, showed the response rate was almost 40% from utilizing that combination of immunotherapy and working by different mechanisms. One is anti–PD-1 and one is anti–CTLA4, but the combination was well tolerated and it actually had significant activity against this tumor. Of course, that was based upon data they had with melanoma and extrapolating moving forward.

Recently presented were the CheckMate-214 data that also saw a significant benefit in patients who received the combination. That was a phase III clinical trial comparing patients with clear-cell renal cell carcinoma in intermediate- and poor-risk patient populations, but they did have favorable-risk patients as well. They looked at sunitinib at the standard dose of 50 mg daily for 4 weeks on, 2 weeks off compared with ipilimumab at 1 mg/kg, nivolumab at 3mg/kg given every 3 weeks for 4 cycles, and continued nivolumab as maintenance therapy.

There was an improvement in all parameters that they were looking for compared with sunitinib in the intermediate- and poor-risk patient populations when it came down to disease-free survival, overall survival, and even some toxicity that seemed to be favoring the combination of immunotherapy as well. There was an issue, of course, when it came down to patients who had favorable risk in that population, where sunitinib seemed to have an improvement in the parameters. But this is the start of a new focus about how we should be considering our patients. It is yet to be FDA approved, but this is how we’re inclined to think now that we’re going to move forward in the next few months.

Nicholas J. Vogelzang, MD, FASCO, FACP: The thing that impressed me with Hammers’ paper that just came out in The Journal of Clinical Oncology is not only the CR rate, which you don’t normally see with sunitinib or a TKI, but also the duration. I think Hans’ paper was published 3 years ago now. Some of these people are still going. That’s impressive. So, I think it’s the new era.

Daniel George, MD: Interesting. Neeraj, at your practice now, you’ve got a lot of experience with TKIs. Is this the new era? Does this change for everybody? How do you integrate this new I-O therapy into the frontline space?

Neeraj Agarwal, MD: As Rob just mentioned, in the favorable-risk category patients, sunitinib outperformed the ipilimumab/nivolumab combination. It was very clear. So, I would not likely consider ipilimumab/nivolumab, the checkpoint inhibitor combination, for favorable-risk patients. I would be very hesitant to do that.

Nicholas J. Vogelzang, MD, FASCO, FACP: That’s only 20% though.

Neeraj Agarwal, MD: Still, I want to start with the risk stratification. So, if you exclude favorable-risk patients, I agree with Dr. Vogelzang. For 80% of patients who definitely belong to poor-risk categories, the ipilimumab/nivolumab combination has shown itself to be superior to sunitinib. And then I start looking at the subgroup analysis, with the caveat that I should not be doing subgroup analysis in a big phase III trial. I feel compelled to do that because I have options, and those options have not been compared with each other and will likely not be compared with each other down the line, at least in the near future.

With those caveats, if I look at the intermediate- and poor-risk patients in the CheckMate trial who did not have PD-L1–expressing tumors, there was really no PFS benefit. Progression-free survival benefit was not there with the ipilimumab/nivolumab combination over sunitinib. On the other hand, if I look at the PD-L1–expressing tumors, defined as more than 1% of PD-L expression, there was a really remarkable PFS benefit: around 22 months with the ipilimumab/nivolumab combination versus 5 months with sunitinib. So, that is something I like to keep in mind.

Secondly, if you look at intent to treat in all intermediate- and poor-risk patients, the PFS benefit was not there if you just combine all of the patients. However, the overall survival benefit was finally presented in the SITC meeting just a few months ago, and it was present in almost all intermediate- and poor-risk patients. But if I look at PD-L1–expressing patients, the overall survival benefit was a lot more remarkable, with a hazard ratio of something in the 0.4 or 0.5 range compared with PD-L1–negative patients, where the hazard ratio was 0.75.

Transcript Edited for Clarity 
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