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 agentsusually 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 receptorsor 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 survivalagainst, 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 cabozantinibagain, 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 reviewand 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.
Advances in Subsequent Therapies Shake Up Sequencing of ccRCC Treatment
April 25th 2024With the approval of belzutifan and other newer data for treating patients with recurrent renal cell carcinoma, the state of subsequent therapies is advancing beyond the reuse of frontline options with impacts on duration of response and quality of life.
Read More
Emphasizing the Need for NGS in Advanced NSCLC to Determine Treatment
April 23rd 2024During a Case-Based Roundtable® event, Joshua Sabari, MD, led a discussion on the need for next-generation sequencing to determine treatment in patients with EGFR-positive advanced non–small cell lung cancer in the first article of a 2-part series.
Read More
Enhancing Precision in Immunotherapy: CD8 PET-Avidity in RCC
March 1st 2024In this episode of Emerging Experts, Peter Zang, MD, highlights research on baseline CD8 lymph node avidity with 89-Zr-crefmirlimab for the treatment of patients with metastatic renal cell carcinoma and response to immunotherapy.
Listen