Positive overall survival (OS) results have been reported from a pivotal phase 3 trial comparing cabozantinib (Cometriq, Exelixis, Inc.) and everolimus (Afinitor, Novartis) in patients with advanced renal cell carcinoma (RCC) who had experienced disease progression after treatment with a vascular epithelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI). In an interim analysis of OS, a secondary endpoint of the trial, the results showed a statistically significant increase in OS among patients treated with cabozantinib compared with those given everolimus.
The FDA recently granted priority review status to the new drug application for cabozantinib and set a Prescription Drug User Fee Act (PDUFA) action date of June 22, 2016.
The regulatory application was based on results from the open-label METEOR trial, which had a primary endpoint of progression-free survival (PFS). The study enrolled 658 patients in 26 countries. The patients were randomly assigned to receive cabozantinib (60 mg/day) or everolimus (10 mg/day). No cross-over was allowed between the study arms.
Cabozantinib was associated with a 42% reduction in the rate of disease progression or death compared with everolimus. Median PFS for cabozantinib was 7.4 months compared with 3.8 months for everolimus (hazard ratio [HR], 0.58; P < 0.001). Cabozantinib also significantly improved the objective response rate compared with everolimus. These findings were published in the New England Journal of Medicine.
A subsequent interim analysis of OS showed a strong trend in OS favoring cabozantinib (HR, 0.67; P = 0.005), although the P value of 0.0019 to achieve statistical significance was not reached at that time. Based on these results and after consulting with the FDA, a second interim analysis was undertaken; the results of this second analysis crossed the boundary for early declaration of statistical significance.
Cabozantinib inhibits the activity of tyrosine kinases, including MET, VEGF receptors, AXL, and RET. These receptor tyrosine kinases are involved in both normal cellular function and pathological processes, such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
Source: Exilixis; February 1, 2017.