Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II).

Purpose: Cediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC).

Patients And Methods: Eligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points.

Results: In all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSION Addition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.