Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment
for patients with advanced colorectal cancer: a double-blind, randomized phase
III study (HORIZON III).
Author(s): Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova
I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B,
Robertson J, Van Cutsem E.
Affiliation(s): Department of Internal Medicine IV, Hematology & Oncology, University Clinic
Halle (Saale), Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40,
06120 Halle, Germany. email@example.com
Publication date & source: 2012, J Clin Oncol. , 30(29):3588-95
PURPOSE: To compare the efficacy of cediranib (a vascular endothelial growth
factor receptor tyrosine kinase inhibitor [VEGFR TKI]) with that of bevacizumab
(anti-VEGF-A monoclonal antibody) in combination with chemotherapy as first-line
treatment for advanced metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS: HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus
FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer] had an adaptive
phase II/III design. Patients randomly assigned 1:1:1 received mFOLFOX6
[oxaliplatin 85 mg/m(2) and leucovorin 400 mg/m(2) intravenously followed by
fluorouracil 400 mg/m(2) intravenously on day 1 and then continuous infusion of
2,400 mg/m(2) over the next 46 hours every 2 weeks] with cediranib (20 or 30 mg
per day) or bevacizumab (5 mg/kg every 14 days). An independent end-of-phase II
analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for
continuation; subsequent patients received mFOLFOX6/cediranib 20 mg or
mFOLFOX6/bevacizumab (randomly assigned 1:1). The primary objective was to
compare progression-free survival (PFS).
RESULTS: In all, 1,422 patients received mFOLFOX6/cediranib 20 mg (n = 709) or
mFOLFOX6/bevacizumab (n = 713). Primary analysis revealed no significant
difference between arms for PFS (hazard ratio [HR], 1.10; 95% CI, 0.97 to 1.25; P
= .119), overall survival (OS; HR, 0.95; 95% CI, 0.82 to 1.10; P = .541), or
overall response rate (46.3% v 47.3%). Median PFS and OS were 9.9 and 22.8 months
for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab. The PFS
upper 95% CI was outside the predefined noninferiority limit (HR < 1.2). Common
adverse events with more than 5% incidence in the cediranib arm included
diarrhea, neutropenia, and hypertension. Cediranib-treated patients completed
fewer chemotherapy cycles than bevacizumab-treated patients (median 10 v 12
cycles). Patient-reported outcomes (PROs) were significantly less favorable in
cediranib-treated versus bevacizumab-treated patients (P < .001).
CONCLUSION: Cediranib activity, in terms of PFS and OS, was comparable to that of
bevacizumab when added to mFOLFOX6; however, the predefined boundary for PFS
noninferiority was not met. The cediranib safety profile was consistent with
previous studies but led to less favorable PROs compared with bevacizumab.
Investigation of oral TKIs in CRC continues.