Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma

Abstract

Background Cabozantinib is an oral small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL; each has been implicated in metastatic renal cell carcinoma (RCC) pathobiology or development of resistance to antiangiogenic drugs. This randomized open-label phase 3 trial evaluated the efficacy of cabozantinib compared to everolimus in RCC patients who progressed after VEGFR-targeted therapy. Methods The trial randomized 658 patients to receive cabozantinib at a dose of 60 mg daily, or everolimus at a dose of 10 mg daily. The primary endpoint was progression-free survival. Secondary efficacy endpoints were overall survival and objective response rate. Results Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The risk of progression or death was 42% lower with cabozantinib compared to everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P < 0.001). Objective response rates were 21% with cabozantinib and 5% with everolimus (P < 0.001). A planned interim analysis showed that overall survival was improved with cabozantinib (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = 0.005) but did not cross the significance boundary. Adverse events (grade 3 or 4, regardless of causality) were reported in 74% of cabozantinib patients and 65% of everolimus patients. Discontinuation of study treatment for adverse events occurred in 9.1% of cabozantinib patients and 10% of everolimus patients. Conclusions Cabozantinib improved progression-free survival compared to everolimus in RCC patients who progressed after VEGFR-targeted therapy.

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer

“…It also allows them to switch to potentially more effective systemic therapies 13,14 . Patients with progression of disease at 14 week (the time of assessment) had a poor outcome justifying this approach (eFigure 1).…”

“…A third sample at progression would have potentially helped address this issue. We explored the effect of pazopanib on PD-L1 and MET expression, both of which are active targets in ccRCC after VEGF targeted therapy 13,14 . Results showed significant decreases to VEGF related proteins such as VEGFR2 as expected 16 .…”

“…Cabozantinib is a MET (and VEGF) inhibitor with activity in VEGF resistant metastatic ccRCC 13 . Pazopanib reduced MET expression, again questioning the value of historical tissue for biomarker expression.…”

“…The median duration of therapy prior to surgery was 13 weeks (range [11][12][13][14]. The median size of the primary tumour before and after pazopanib was 10.…”

Targeted therapy: An elusive cancer target

“…Motzer, along with Escudier, also found that cabozantinib led to longer survival than everolimus 4 . "We do not know for certain why the results were so good, " says Motzer.…”