Cabozantinib is an oral tyrosine kinase inhibitor targeting both the vascular endothelial growth factor receptor (VEGFR) and the kinases MET and AXL. All these proteins were shown to play a role in the pathogenesis of advanced renal cell carcinoma (RCC), making cabozantinib an interesting therapeutic option for these patients. Results of the phase III METEOR trial demonstrated that cabozantinib significantly delays progression of disease compared to everolimus in patients with advanced RCC. In addition, a trend towards an improved survival with cabozantinib was reported.
Drugs directed against VEGFR are very effective in the first-line therapy of advanced RCC. However, most patients will eventually develop resistance against these agents leading to disease progression. As indicated before, cabozantinib also blocks the activity of MET and AXL, two proteins involved in escape mechanisms of VEGFR inhibition. In the phase III METEOR trial, a total of 650 patients with advanced RCC and with disease progression after anti-VEGFR therapy, were randomized between cabozantinib (60 mg per day), or everolimus (10 mg per day). The primary endpoint of the study was progression-free survival (PFS), while objective response rate (ORR) and overall survival (OS) were the key secondary endpoint for efficacy. The presented PFS analysis at the 2015 European Cancer Congress included data for the first 375 patients randomized in the study.
For patients in the cabozantinib arm, the reported median PFS was 7.4 months as compared to 3.8 months for patients allocated to the everolimus treatment. This translates into a significant 42% reduction in the risk of disease progression or death when patients were treated with cabozantinib rather than with everolimus (HR[95%CI]: 0.58[0.45-0.75]; p< 0.001). The ORR was 21% in the cabozantinib arm, which was significantly better than the 5% ORR seen with everolimus (p< 0.001). An interim analysis for OS in the entire study cohort of 650 patients demonstrated that patients on cabozantinib lived longer than patients on everolimus (HR[95%CI]: 0.67[0.51-0.89]; p= 0.005). However, this difference was not sufficient to cross the predefined border for significance in this interim analysis.
The PFS advantage observed with cabozantinib did come at the cost of increased toxicity. In fact, the incidence of grade 3/4 adverse events was 68% with cabozantinib as compared to 58% with everolimus. The most common high-grade (3/4) adverse events with cabozantinib were hypertension (15%), diarrhea (11%), and fatigue, while the grade 3/4 adverse events most frequently seen with everolimus were anemia (16%), fatigue (7%), and hyperglycemia (5%). In general, the adverse events in this study were manageable with dose reductions. Such dose reductions were needed in 60% of patients treated with cabozantinib and in 25% of everolimus treated patients. In total, 9% of patients on cabozantinib and 10% of patients on everolimus needed to discontinue therapy due to adverse events.
In summary, the METEOR trial demonstrates that cabozantinib delays the disease progression of advanced RCC patients who progressed after first-line anti-VEGFR therapy, compared to everolimus. In addition, a higher ORR and a (non-significantly) longer OS were seen with cabozantinib. Based on these convincing data, the METEOR trial was stopped prematurely. Together with the results of the Checkmate-025 study, also presented at ECC 2015 and demonstrating superior OS with nivolumab in this setting, the results of METEOR will significantly impact the treatment algorithm for recurrent advanced RCC.
Choueiri T, et al. Cabozantinib versus everolimus in patients with advanced renal cell carcinoma: Results of the randomized phase 3 METEOR trial. Presented at ECC 2015; Abstract #LBA4.