Select Topic:
Browse by Series:

mRCC: How an Approved I-O Regimen Impacts Treatment

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: The rationale for checkpoint combination is really just a difference in complementary ways to stimulate immune response. While checkpoint inhibitors are largely directed against PD-1 or PD-L1, adding in a CTLA4 blockade should augment T-cell stimulation, which is the whole trick of immunotherapy. While there’s certainly more toxicity to combination therapy, I tell patients that PD-1 monotherapy is about the easiest drug I give in terms of side effects. It’s really easy.

The ipilimumab /nivolumab combination therapy is not easy, right? I wouldn’t necessarily call it easy; it’s certainly not the easiest. There is some toxicity cost, but although they’ve not been directly compared, it’s clear to me that combination therapy is more active. There are more complete responses, probably deeper and more durable responses.

David F. McDermott, MD: CheckMate-214 was a very interesting result for our patients. Prior to that study, we had nivolumab, or PD-1 blockade, approved for patients who had failed VEGF therapy. CheckMate-214 was an attempt to bring PD-1 blockade into the front line by combining it with CTLA4 blockade, ipilimumab. That’s an approved and effective strategy in melanoma patients.

We were bringing that regimen, or that combination, to our patients with kidney cancer and comparing it to the standard of care, which is sunitinib. That head-to-head phase III trial was a very positive study. It met most of its primary endpoints, including a significant improvement in overall response rate, overall survival, and quality of life, which favored the combination regimen. Interestingly, the side effect profile, when you look at grade 3/4 toxicity, was actually less severe in the combination than in sunitinib, which surprised many of us.

We saw more clinical efficacy than we expected, and less toxicity. Now, the toxicity may have been less in part because the regimen in kidney cancer is different than the regimen in melanoma, where for melanoma, the dose of ipilimumab is higher and nivolumab is lower. In kidney cancer, it’s the inverse of that. There’s more nivolumab driving the benefit in patients with kidney cancer, and that’s improved the toxicity profile and the applicability in the clinic. It has made it easier to give. These results are not just statistically significant, but I think they’re clinically meaningful. We’re finally seeing overall survival, which we struggled to get in our patients with advanced kidney cancer with prior treatments.

Probably most importantly for me is that we’re not only seeing responses, but we’re seeing complete responses in approximately 10% of patients. In the past, and with immune therapies like high-dose interluken-2, it’s those complete responses that have actually been able to develop a remission of the disease. Some of those patients are actually cured. It’ll be very interesting to see, as we follow the ipilimumab/nivolumab story, whether those patients with those deep responses are actually entering remissions of their disease, which is the first step to curing their advanced cancer. This is very exciting.

One important part of the trial that is also interesting is that the benefit with ipilimumab/nivolumab was greatest in the worst prognostic groups, like intermediate- and poor-risk patients, as I mentioned earlier. The good-risk patients, at least in the early markers of efficacy, did better with sunitinib. Both groups benefited, and we got a sense that maybe one group could start off with a VEGF-targeted strategy, while intermediate- and poor-risk patients might benefit from an I-O/I-O [immuno-oncology] combination. But we saw benefits across the board for patients on the trial.

Brian Rini, MD: Bevacizumab plus interferon was the original VEGF plus I/O therapy back in the day. It wasn’t used much after its approval, although it was clearly active, in part because of the interferon toxicity. Number one, interferon is subcutaneous. Nobody really likes to do that. It’s administered 3 times a week, and it produces flu-like symptoms. It wasn’t a great partner for bevacizumab. Bevacizumab by itself is active and really well tolerated, but the interferon dragged it down. It wasn’t used much even after approval, and I’m not sure anybody’s really using it today. With these new combinations, no way.

Transcript Edited for Clarity 
Slider Left
Slider Right


Transcript: 

Brian Rini, MD: The rationale for checkpoint combination is really just a difference in complementary ways to stimulate immune response. While checkpoint inhibitors are largely directed against PD-1 or PD-L1, adding in a CTLA4 blockade should augment T-cell stimulation, which is the whole trick of immunotherapy. While there’s certainly more toxicity to combination therapy, I tell patients that PD-1 monotherapy is about the easiest drug I give in terms of side effects. It’s really easy.

The ipilimumab /nivolumab combination therapy is not easy, right? I wouldn’t necessarily call it easy; it’s certainly not the easiest. There is some toxicity cost, but although they’ve not been directly compared, it’s clear to me that combination therapy is more active. There are more complete responses, probably deeper and more durable responses.

David F. McDermott, MD: CheckMate-214 was a very interesting result for our patients. Prior to that study, we had nivolumab, or PD-1 blockade, approved for patients who had failed VEGF therapy. CheckMate-214 was an attempt to bring PD-1 blockade into the front line by combining it with CTLA4 blockade, ipilimumab. That’s an approved and effective strategy in melanoma patients.

We were bringing that regimen, or that combination, to our patients with kidney cancer and comparing it to the standard of care, which is sunitinib. That head-to-head phase III trial was a very positive study. It met most of its primary endpoints, including a significant improvement in overall response rate, overall survival, and quality of life, which favored the combination regimen. Interestingly, the side effect profile, when you look at grade 3/4 toxicity, was actually less severe in the combination than in sunitinib, which surprised many of us.

We saw more clinical efficacy than we expected, and less toxicity. Now, the toxicity may have been less in part because the regimen in kidney cancer is different than the regimen in melanoma, where for melanoma, the dose of ipilimumab is higher and nivolumab is lower. In kidney cancer, it’s the inverse of that. There’s more nivolumab driving the benefit in patients with kidney cancer, and that’s improved the toxicity profile and the applicability in the clinic. It has made it easier to give. These results are not just statistically significant, but I think they’re clinically meaningful. We’re finally seeing overall survival, which we struggled to get in our patients with advanced kidney cancer with prior treatments.

Probably most importantly for me is that we’re not only seeing responses, but we’re seeing complete responses in approximately 10% of patients. In the past, and with immune therapies like high-dose interluken-2, it’s those complete responses that have actually been able to develop a remission of the disease. Some of those patients are actually cured. It’ll be very interesting to see, as we follow the ipilimumab/nivolumab story, whether those patients with those deep responses are actually entering remissions of their disease, which is the first step to curing their advanced cancer. This is very exciting.

One important part of the trial that is also interesting is that the benefit with ipilimumab/nivolumab was greatest in the worst prognostic groups, like intermediate- and poor-risk patients, as I mentioned earlier. The good-risk patients, at least in the early markers of efficacy, did better with sunitinib. Both groups benefited, and we got a sense that maybe one group could start off with a VEGF-targeted strategy, while intermediate- and poor-risk patients might benefit from an I-O/I-O [immuno-oncology] combination. But we saw benefits across the board for patients on the trial.

Brian Rini, MD: Bevacizumab plus interferon was the original VEGF plus I/O therapy back in the day. It wasn’t used much after its approval, although it was clearly active, in part because of the interferon toxicity. Number one, interferon is subcutaneous. Nobody really likes to do that. It’s administered 3 times a week, and it produces flu-like symptoms. It wasn’t a great partner for bevacizumab. Bevacizumab by itself is active and really well tolerated, but the interferon dragged it down. It wasn’t used much even after approval, and I’m not sure anybody’s really using it today. With these new combinations, no way.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Rapid Reviews in Oncology®: Practice-Changing Data in Acute Myeloid Leukemia: A Rapid Update From Atlanta OnlineDec 21, 20182.0
Community Practice Connections™: 2nd Annual European Congress on Hematology™: Focus on Lymphoid MalignanciesDec 30, 20182.0
Publication Bottom Border
Border Publication
x