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A Novel Approach: TKI/I-O Combinations in RCC

Insights From: Brian Rini,MD, Cleveland Clinic Main Campus; David F. McDermott, MD, Harvard Cancer Center
Published: Monday, Dec 10, 2018



Transcript: 

Brian Rini, MD: TKI/I-O combinations in kidney cancer appear to be very active, perhaps the most active of the combinations. There were 2 phase I/II studies. One was with axitinib plus avelumab, a PD-L1 [programmed death-ligand 1] inhibitor, that showed a high response rate in the phase I setting, about 60% or so. A phase III trial comparing that combination of Sutent [sunitinib], called JAVELIN, is being reported at this year’s ESMO [European Society for Medical Oncology] meeting, and we know just through the press release that it showed a progression-free survival [PFS] advantage. We know that these combinations are active. They appear to have higher response rates and longer progression-free survival than ipilimumab/nivolumab, if I could compare across trials a little bit, probably because of that VEGF inhibitor component.

Another combination is axitinib plus pembrolizumab, also with very high response rates and long progression-free survival in a phase I/II study. We don’t yet have the phase III study data, although 2 days ago there was a press release that the study was also positive for not only PFS but overall survival, which I think was a pleasant surprise to many people. These regimens may be even more active than we thought, and I think once the full data are out, it’s going to shape the landscape a lot.

David F. McDermott, MD: Over the last 2 years, we’ve attempted to combine VEGF and PD-1 [programmed cell death protein 1] blockade in several phase I trials with expansion cohorts, and we’ve seen these combinations show interesting results that are now leading to positive phase III trials. One of those combinations was lenvatinib/pembrolizumab. When we put those 2 agents together, the response rate was close to 70% in an expansion cohort. That combination is now being looked at in a phase III trial, and we’ll see how it holds up to some of these other combinations that have produced positive phase III results: for example, axitinib/pembrolizumab and atezolizumab/bevacizumab. We’ll probably have 4 or 5 different positive phase III trials about a year from now. We’ll have to figure which combination to use for which patient. It’s not going to be easy, I think, to distinguish between these active regimens.

Brian Rini, MD: CheckMate 9ER involves cabozantinib plus nivolumab. There was a cabozantinib/ipilimumab/nivolumab arm that was closed, so it’s just cabozantinib/nivolumab versus Sutent. It’s similar to the other combinations, a TKI and I/O put together. There’s clearly going to be activity. I believe it’s still accruing now whereas the others are finished and have reported, but it’s the same concept.

IMmotion151 was a randomized phase III trial of atezolizumab plus bevacizumab compared to Sutent that has been reported in abstract form, so far showing a progression-free survival advantage as well as a response rate advantage, but no mature data of overall survival yet. It’s yet another active combination. I think that combination’s calling card is as much tolerability as activity. It’s really well tolerated. We talked about ipilimumab/nivolumab, and even the TKI combos, having some tolerability issues, especially for frailer patients. I think atezolizumab/bevacizumab would be tolerated by just about anybody.

Transcript Edited for Clarity
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Transcript: 

Brian Rini, MD: TKI/I-O combinations in kidney cancer appear to be very active, perhaps the most active of the combinations. There were 2 phase I/II studies. One was with axitinib plus avelumab, a PD-L1 [programmed death-ligand 1] inhibitor, that showed a high response rate in the phase I setting, about 60% or so. A phase III trial comparing that combination of Sutent [sunitinib], called JAVELIN, is being reported at this year’s ESMO [European Society for Medical Oncology] meeting, and we know just through the press release that it showed a progression-free survival [PFS] advantage. We know that these combinations are active. They appear to have higher response rates and longer progression-free survival than ipilimumab/nivolumab, if I could compare across trials a little bit, probably because of that VEGF inhibitor component.

Another combination is axitinib plus pembrolizumab, also with very high response rates and long progression-free survival in a phase I/II study. We don’t yet have the phase III study data, although 2 days ago there was a press release that the study was also positive for not only PFS but overall survival, which I think was a pleasant surprise to many people. These regimens may be even more active than we thought, and I think once the full data are out, it’s going to shape the landscape a lot.

David F. McDermott, MD: Over the last 2 years, we’ve attempted to combine VEGF and PD-1 [programmed cell death protein 1] blockade in several phase I trials with expansion cohorts, and we’ve seen these combinations show interesting results that are now leading to positive phase III trials. One of those combinations was lenvatinib/pembrolizumab. When we put those 2 agents together, the response rate was close to 70% in an expansion cohort. That combination is now being looked at in a phase III trial, and we’ll see how it holds up to some of these other combinations that have produced positive phase III results: for example, axitinib/pembrolizumab and atezolizumab/bevacizumab. We’ll probably have 4 or 5 different positive phase III trials about a year from now. We’ll have to figure which combination to use for which patient. It’s not going to be easy, I think, to distinguish between these active regimens.

Brian Rini, MD: CheckMate 9ER involves cabozantinib plus nivolumab. There was a cabozantinib/ipilimumab/nivolumab arm that was closed, so it’s just cabozantinib/nivolumab versus Sutent. It’s similar to the other combinations, a TKI and I/O put together. There’s clearly going to be activity. I believe it’s still accruing now whereas the others are finished and have reported, but it’s the same concept.

IMmotion151 was a randomized phase III trial of atezolizumab plus bevacizumab compared to Sutent that has been reported in abstract form, so far showing a progression-free survival advantage as well as a response rate advantage, but no mature data of overall survival yet. It’s yet another active combination. I think that combination’s calling card is as much tolerability as activity. It’s really well tolerated. We talked about ipilimumab/nivolumab, and even the TKI combos, having some tolerability issues, especially for frailer patients. I think atezolizumab/bevacizumab would be tolerated by just about anybody.

Transcript Edited for Clarity
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