ONCAlert | Upfront Therapy for mRCC

mRCC: Decision Making for VEGF TKIs

Martin H. Voss, MD
Published Online:12:23 PM, Fri July 27, 2018

Martin H. Voss, MD: If we look beyond the first-line setting, we have a number of agents to consider in patients who have progressed on first-line therapy, be it kinase inhibitor therapy or I-O therapy. And it has become somewhat difficult for physicians to decide between the many options that we have on the shelf. The NCCN committee gives category 1 support to 4 regimens in the second-line setting presently, and that is based on randomized data that have previously been published. The 4 choices that they endorse are single-agent cabozantinib in patients who have not previously received cabozantinib; single-agent axitinib, based on the AXIS trial that was published many years ago; the combination of lenvatinib/everolimus, based on a phase II/III arm randomized trial, the Eisai 205 study, that put that combination on the market; and then lastly, nivolumab monotherapy based on CheckMate-025.

What’s confusing here is that these endorsements—and more relevantly, these trials—were conducted prior to the new approvals in the first-line setting. So, we have discussed now that we have cabozantinib and ipilimumab/nivolumab as considerations in the first-line therapy. We have no data and no expert recommendations to guide for any of these second-line regimens in patients who have received one of these two in the first-line setting. Now, nonetheless, we can use the second-line data for decision making. We can think about how these kinase inhibitors are different. So, the different TKIs that are out there all inhibit VEGFR-2 as their principal target. Additionally, they have other targets, at least some of them do. Axitinib, which has been on the market the longest, is a very pure VEGF receptor-2 kinase inhibitor. It’s kind of like a sniper gun that goes very potently and very selectively after VEGFR-2.

Cabozantinib, which we’ve talked about quite a bit now, in addition to VEGFR-2, inhibits 2 relevant kinases, AXL and MET, both of which have been shown to mediate angiogenesis and VEGF-independent ways. So, the rationale here is that cancer cells, once they become independent of VEGF signaling, need to find other ways to build neovasculature. And it has been shown in preclinical models but also based on patient samples that kinase inhibitor pretreated tumors upregulate AXL and MET as mechanisms of resistance. So, cabozantinib has exploited these as targets, and based on the randomized METEOR study, it was much more efficacious than the mTOR inhibitor, everolimus, in TKI-pretreated patients.

Lenvatinib, which is FDA approved in combination with everolimus, in addition to VEGF receptor-2, blocks fibroblast growth factor receptor, so FGFR-1 through FGFR-4. Again, FGFR signaling is thought to mediate angiogenesis, independent of VEGF. As I mentioned, it has been approved in the combination with the mTOR inhibitor, everolimus, and it’s the only targeted combination that is currently on the market. When we think about these 4 options that are supported by the NCCN and that all have randomized data that led to their approval, it’s important to note that none of these 4 have been compared with one another. So, they have all been compared to older standards. Axitinib was superior to sorafenib, and the 3 other regimens that we’ve talked about were all superior to everolimus. But none of the 4 have been compared with one another.

Transcript edited for clarity.

Martin H. Voss, MD: If we look beyond the first-line setting, we have a number of agents to consider in patients who have progressed on first-line therapy, be it kinase inhibitor therapy or I-O therapy. And it has become somewhat difficult for physicians to decide between the many options that we have on the shelf. The NCCN committee gives category 1 support to 4 regimens in the second-line setting presently, and that is based on randomized data that have previously been published. The 4 choices that they endorse are single-agent cabozantinib in patients who have not previously received cabozantinib; single-agent axitinib, based on the AXIS trial that was published many years ago; the combination of lenvatinib/everolimus, based on a phase II/III arm randomized trial, the Eisai 205 study, that put that combination on the market; and then lastly, nivolumab monotherapy based on CheckMate-025.

What’s confusing here is that these endorsements—and more relevantly, these trials—were conducted prior to the new approvals in the first-line setting. So, we have discussed now that we have cabozantinib and ipilimumab/nivolumab as considerations in the first-line therapy. We have no data and no expert recommendations to guide for any of these second-line regimens in patients who have received one of these two in the first-line setting. Now, nonetheless, we can use the second-line data for decision making. We can think about how these kinase inhibitors are different. So, the different TKIs that are out there all inhibit VEGFR-2 as their principal target. Additionally, they have other targets, at least some of them do. Axitinib, which has been on the market the longest, is a very pure VEGF receptor-2 kinase inhibitor. It’s kind of like a sniper gun that goes very potently and very selectively after VEGFR-2.

Cabozantinib, which we’ve talked about quite a bit now, in addition to VEGFR-2, inhibits 2 relevant kinases, AXL and MET, both of which have been shown to mediate angiogenesis and VEGF-independent ways. So, the rationale here is that cancer cells, once they become independent of VEGF signaling, need to find other ways to build neovasculature. And it has been shown in preclinical models but also based on patient samples that kinase inhibitor pretreated tumors upregulate AXL and MET as mechanisms of resistance. So, cabozantinib has exploited these as targets, and based on the randomized METEOR study, it was much more efficacious than the mTOR inhibitor, everolimus, in TKI-pretreated patients.

Lenvatinib, which is FDA approved in combination with everolimus, in addition to VEGF receptor-2, blocks fibroblast growth factor receptor, so FGFR-1 through FGFR-4. Again, FGFR signaling is thought to mediate angiogenesis, independent of VEGF. As I mentioned, it has been approved in the combination with the mTOR inhibitor, everolimus, and it’s the only targeted combination that is currently on the market. When we think about these 4 options that are supported by the NCCN and that all have randomized data that led to their approval, it’s important to note that none of these 4 have been compared with one another. So, they have all been compared to older standards. Axitinib was superior to sorafenib, and the 3 other regimens that we’ve talked about were all superior to everolimus. But none of the 4 have been compared with one another.

Transcript edited for clarity.
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