ONCAlert | 2018 ASCO Annual Meeting

Recent Advances in Metastatic Kidney Cancer

Toni Choueiri, MD
Published Online:12:49 PM, Fri March 23, 2018

Toni Choueiri, MD: Well, the field is changing at a rapid pace in RCC, and first in metastatic renal cell cancer, kidney cancer. So, we had, for the past 10 to 15 years, targeted agents—usually oral agents, drugs that target the VEGF receptor—and mTOR inhibitors. And for the past few years, immunotherapy came in to treat renal cell carcinoma, and there was the introduction of nivolumab in patients who progressed on prior lines of treatment. And now there are several immune checkpoint blockers, mostly PD-1 and PD-L1 inhibitors—but also, to some degree, CTLA4 inhibitors were making their way in kidney cancer in the advanced form, mostly through combination therapies with an immuno-oncology drug or with a TKI.

Cabozantinib is an interesting drug. It’s actually a tyrosine kinase inhibitor that is an important VEFG receptor inhibitor. But in addition to that, it does have some properties against other receptors such as MET and AXL. And there’s a preclinical evidence that these 2 receptors—or these 2 pathways, if you want, the MET and the AXL pathways—could be involved in a mechanism of resistance that happens at the beginning or after exposure to VEGF receptor blockade.

Initially, cabozantinib showed activity in an early phase I trial in heavily pretreated patients and was taken to a second-line setting in patients who progress on a VEGF tyrosine kinase inhibitor. That was the METEOR study, a large, well-powered phase III trial with primary endpoint progression-free survival—against, at that time, a standard therapy: oral mTOR inhibitor everolimus, which was FDA approved in 2009.

And the study met its primary endpoint, and the progression-free survival was superior, almost double with cabozantinib compared with everolimus. And in addition, the response rates were higher and statistically significant. And more important even, the secondary endpoint of overall survival was significant. So, that led to the approval of cabozantinib in the second-line or later-line setting.

Having said so and in parallel, there was a trial in untreated patients who are at poor or intermediate risk by the IMDC criteria, which is around 75% to 80% of all comers, that investigated the activity of cabozantinib—again, using progression-free survival as a primary endpoint versus sunitinib. Sunitinib has been a standard and the most commonly and widely used VEGF tyrosine kinase inhibitor for the past 10 years. And the study met its primary endpoint, though it was a small randomized phase II, but it showed a progression-free survival advantage with cabozantinib over sunitinib, both clinically relevant and statistically significant.

Then the authors went and did a center review of these scans because that study was run by Alliance, the primary endpoint was investigator review—and here we go again, there was a benefit both statistically significant and clinically relevant; hazard ratio, 0.48. The response rates also were higher with cabozantinib compared with sunitinib. The study was not powered for overall survival, and actually, that secondary endpoint was not met.

Toxicities also were not different between sunitinib and cabozantinib, although there was no quality of life assessment; it was just comparing all-grade and high-grade toxicities. And this led to the approval for a change of label and the approval of cabozantinib in the frontline setting.

Transcript edited for clarity.
 

Toni Choueiri, MD: Well, the field is changing at a rapid pace in RCC, and first in metastatic renal cell cancer, kidney cancer. So, we had, for the past 10 to 15 years, targeted agents—usually oral agents, drugs that target the VEGF receptor—and mTOR inhibitors. And for the past few years, immunotherapy came in to treat renal cell carcinoma, and there was the introduction of nivolumab in patients who progressed on prior lines of treatment. And now there are several immune checkpoint blockers, mostly PD-1 and PD-L1 inhibitors—but also, to some degree, CTLA4 inhibitors were making their way in kidney cancer in the advanced form, mostly through combination therapies with an immuno-oncology drug or with a TKI.

Cabozantinib is an interesting drug. It’s actually a tyrosine kinase inhibitor that is an important VEFG receptor inhibitor. But in addition to that, it does have some properties against other receptors such as MET and AXL. And there’s a preclinical evidence that these 2 receptors—or these 2 pathways, if you want, the MET and the AXL pathways—could be involved in a mechanism of resistance that happens at the beginning or after exposure to VEGF receptor blockade.

Initially, cabozantinib showed activity in an early phase I trial in heavily pretreated patients and was taken to a second-line setting in patients who progress on a VEGF tyrosine kinase inhibitor. That was the METEOR study, a large, well-powered phase III trial with primary endpoint progression-free survival—against, at that time, a standard therapy: oral mTOR inhibitor everolimus, which was FDA approved in 2009.

And the study met its primary endpoint, and the progression-free survival was superior, almost double with cabozantinib compared with everolimus. And in addition, the response rates were higher and statistically significant. And more important even, the secondary endpoint of overall survival was significant. So, that led to the approval of cabozantinib in the second-line or later-line setting.

Having said so and in parallel, there was a trial in untreated patients who are at poor or intermediate risk by the IMDC criteria, which is around 75% to 80% of all comers, that investigated the activity of cabozantinib—again, using progression-free survival as a primary endpoint versus sunitinib. Sunitinib has been a standard and the most commonly and widely used VEGF tyrosine kinase inhibitor for the past 10 years. And the study met its primary endpoint, though it was a small randomized phase II, but it showed a progression-free survival advantage with cabozantinib over sunitinib, both clinically relevant and statistically significant.

Then the authors went and did a center review of these scans because that study was run by Alliance, the primary endpoint was investigator review—and here we go again, there was a benefit both statistically significant and clinically relevant; hazard ratio, 0.48. The response rates also were higher with cabozantinib compared with sunitinib. The study was not powered for overall survival, and actually, that secondary endpoint was not met.

Toxicities also were not different between sunitinib and cabozantinib, although there was no quality of life assessment; it was just comparing all-grade and high-grade toxicities. And this led to the approval for a change of label and the approval of cabozantinib in the frontline setting.

Transcript edited for clarity.
 
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