BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial 
growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of 
gemcitabine with or without axitinib in advanced pancreatic cancer suggested 
increased overall survival in axitinib-treated patients. On the basis of these 
results, we aimed to assess the effect of treatment with gemcitabine plus 
axitinib on overall survival in a phase 3 trial.
METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible 
patients had metastatic or locally advanced pancreatic adenocarcinoma, no 
uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology 
Group performance status 0 or 1. Patients, stratified by disease extent 
(metastatic vs locally advanced), were randomly assigned (1:1) to receive 
gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus 
either axitinib or placebo. Axitinib or placebo were administered orally with 
food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 
10 mg twice daily if well tolerated. A centralised randomisation procedure was 
used to assign patients to each treatment group, with randomised permuted blocks 
within strata. Patients, investigators, and the trial sponsor were masked to 
treatment assignments. The primary endpoint was overall survival. All efficacy 
analyses were done in all patients assigned to treatment groups for whom data 
were available; safety and treatment administration and compliance assessments 
were based on treatment received. This study is registered at 
ClinicalTrials.gov, number NCT00471146.
FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled 
and assigned to treatment groups (316 axitinib, 316 placebo). At an interim 
analysis in January, 2009, the independent data monitoring committee concluded 
that the futility boundary had been crossed. Median overall survival was 8·5 
months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for 
two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; 
hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common 
grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine 
plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), 
abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and 
anorexia (19 [6%] and 11 [4%]).
INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall 
survival in advanced pancreatic cancer. These results add to increasing evidence 
that targeting of VEGF signalling is an ineffective strategy in this disease.
FUNDING: Pfizer.