Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study

Summary

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/m² 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.

Introduction

The prognosis for patients with advanced pancreatic adenocarcinoma is poor, and gemcitabine, the standard of care, offers only slight benefit.1, 2 Despite extensive research, combination regimens with gemcitabine and cytotoxic or molecularly targeted agents have not significantly improved outcomes compared with gemcitabine monotherapy.³ The addition of erlotinib to gemcitabine resulted in a significant but very small improvement in overall survival.3, 4 There is a pressing need for new treatment options for this disease.

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3.⁵ A randomised phase 2 study⁶ of 103 patients with locally advanced and metastatic pancreatic adenocarcinoma showed an improvement in median overall survival (6·9 vs 5·6 months; hazard ratio [HR] 0·71, 95% CI 0·44–1·13) and a greater 1-year survival (37% vs 24%) for axitinib plus gemcitabine versus gemcitabine alone. Although not significant, the apparent increase in survival in the combination group provided the rationale for a larger phase 3 study of this regimen. We aimed to assess overall survival in patients with advanced pancreatic cancer treated with gemcitabine plus axitinib versus gemcitabine plus placebo.