A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers

Abstract

Background: Blockade of the vascular endothelial growth factor (VEGF) pathway shows evidence of activity in gastro-oesophageal (GE) and oesophageal cancer. We investigated the efficacy of sunitinib, a multikinase VEGF inhibitor, in patients with relapsed/refractory GE/oesophageal cancer.

Methods: This was a single-stage Fleming phase II study. The primary end point was progression-free survival (PFS) at 24 weeks. If five or more patients out of a total of 25 were free of progressive disease at 24 weeks, sunitinib would be recommended for further study. Patients received sunitinib 37.5 mg orally daily and imaged every 6 weeks. Exploratory correlative analysis included serum growth factors, tumour gene expression and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Results: Twenty-five evaluable patients participated in the study. Progression-free survival at 24 weeks was 8% (n=2 patients; confidence interval (CI): 95% 1.4-22.5%), and the duration of best response for the patients was 23 and 72 weeks. Ten patients (42%) had stable disease (SD) for >10 weeks. Overall response rate is 13%. Median PFS is 7 weeks (95% CI: 5.6-11.4 weeks) and the median overall survival is 17 weeks (95% CI: 8.9-25.3 weeks). Most common grade 3/4 toxicities included fatigue (24%), anaemia (20%) thrombocytopenia (16%), and leucopenia (16%). No patients discontinued therapy due to toxicity. Serum VEGF-A and -C levels, tumour complement factor B (CFB) gene expression, and DCE-MRI correlated with clinical benefit, defined as SD or better as best response.

Conclusion: Sunitinib is well tolerated but only a select subgroup of patients benefited. Serum VEGF-A and -C may be early predictors of benefit. On this study, patients with clinical benefit from sunitinib had higher tumour CFB expression, and thus has identified CFB as a potential predictor for efficacy of anti-angiogenic therapy. These findings need validation from future prospective trials.

Figures

Figure 1

Waterfall plot of patients' best response.

Figure 2

Serum growth factor levels. Patients who had PD are in red and patients who had clinical benefit (SD or PR) are in black. Patients with PD were found to have significantly higher VEGF-A levels at week 2, as compared with baseline. Patients who did derive clinical benefit from sunitinib were found to have statistically significant higher VEGF-C levels at baseline, and decrease at 2 weeks.

Figure 3

Heat map of CFB gene isoform expression levels. Patients who did not have disease progression (SD+PR) are depicted in orange, whereas those with PD are in green. Expression levels red=high, blue=low. Collectively, there was a statistical trend towards higher expression of CFB in those patients who benefited from VEGFR inhibition.