ONCAlert | Upfront Therapy for mRCC

Role for Everolimus in mRCC Treatment?

Martin H. Voss, MD
Published Online:12:24 PM, Fri July 27, 2018

Martin H. Voss, MD: It’s difficult to decide between the many options that are there, and I’ve mentioned that out of the efficacious regimens that are there and that are being commonly used, there isn’t one clear winner that the data suggest should be uniformly used in the second-line setting. But the 1 message that has come across quite clearly is that single-agent everolimus therapy—everolimus being an oral mTOR inhibitor that has been on the market for TKI-pretreated kidney cancer for many years—should no longer be considered a standard of care in the second-line setting and likely also not in the third-line setting. Everolimus was inferior on randomized trials when compared with cabozantinib. It was inferior to single-agent nivolumab. It was inferior to the combination of lenvatinib/everolimus, and indeed also to lenvatinib monotherapy.

So, presently, it does not have a defined role in TKI-pretreated patients. It has been tested also in the first-line setting. There was the phase II RECORD-3 trial, that was published in the Journal of Clinical Oncology a couple of years ago, that tested its utility in the first-line setting and that was a noninferiority trial that tried to prove its noninferiority to sunitinib in untreated patients regardless of risk status. That was a negative study. It was indeed found to be inferior.

Everolimus has been tested intensely in non–clear cell kidney cancer in that it’s back to 2 randomized studies previously published. The ASPEN and the ESPN trials both tested sunitinib versus everolimus in untreated metastatic non–clear cell kidney cancer variants. Both of these studies statistically were conceptualized to prove superiority to everolimus, and neither of them were able to do so. So, everolimus was not deemed superior to sunitinib in the primary endpoint analyses for both of these randomized studies. Again, while it has shown some efficacy across various non–clear cell phenotypes—specifically chromophobe kidney cancers and also, to some extent, papillary kidney cancers—there was not the sense that it was clearly superior to kinase inhibitor therapy. And, again, it would not be considered a standard in that setting.

Transcript edited for clarity.

Martin H. Voss, MD: It’s difficult to decide between the many options that are there, and I’ve mentioned that out of the efficacious regimens that are there and that are being commonly used, there isn’t one clear winner that the data suggest should be uniformly used in the second-line setting. But the 1 message that has come across quite clearly is that single-agent everolimus therapy—everolimus being an oral mTOR inhibitor that has been on the market for TKI-pretreated kidney cancer for many years—should no longer be considered a standard of care in the second-line setting and likely also not in the third-line setting. Everolimus was inferior on randomized trials when compared with cabozantinib. It was inferior to single-agent nivolumab. It was inferior to the combination of lenvatinib/everolimus, and indeed also to lenvatinib monotherapy.

So, presently, it does not have a defined role in TKI-pretreated patients. It has been tested also in the first-line setting. There was the phase II RECORD-3 trial, that was published in the Journal of Clinical Oncology a couple of years ago, that tested its utility in the first-line setting and that was a noninferiority trial that tried to prove its noninferiority to sunitinib in untreated patients regardless of risk status. That was a negative study. It was indeed found to be inferior.

Everolimus has been tested intensely in non–clear cell kidney cancer in that it’s back to 2 randomized studies previously published. The ASPEN and the ESPN trials both tested sunitinib versus everolimus in untreated metastatic non–clear cell kidney cancer variants. Both of these studies statistically were conceptualized to prove superiority to everolimus, and neither of them were able to do so. So, everolimus was not deemed superior to sunitinib in the primary endpoint analyses for both of these randomized studies. Again, while it has shown some efficacy across various non–clear cell phenotypes—specifically chromophobe kidney cancers and also, to some extent, papillary kidney cancers—there was not the sense that it was clearly superior to kinase inhibitor therapy. And, again, it would not be considered a standard in that setting.

Transcript edited for clarity.
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