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

C. Wu, S. Mikhail, L. Wei, C. Timmers, S. Tahiri, A. Neal, J. Walker, S. El-Dika, M. Blazer, J. Rock, D. J. Clark, X. Yang, J. L. Chen, J. Liu, M. V. Knopp, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)220-225
Number of pages6
JournalBritish Journal of Cancer
Volume113
Issue number2
DOIs
StatePublished - Jul 14 2015
Externally publishedYes

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Esophageal Neoplasms
Vascular Endothelial Growth Factor A
Complement Factor B
Vascular Endothelial Growth Factor C
Disease-Free Survival
Confidence Intervals
Serum
Magnetic Resonance Imaging
sunitinib
Gene Expression
Neoplasms
Leukopenia
Thrombocytopenia
Fatigue
Anemia
Intercellular Signaling Peptides and Proteins
Survival
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers. / Wu, C.; Mikhail, S.; Wei, L.; Timmers, C.; Tahiri, S.; Neal, A.; Walker, J.; El-Dika, S.; Blazer, M.; Rock, J.; Clark, D. J.; Yang, X.; Chen, J. L.; Liu, J.; Knopp, M. V.; Bekaii-Saab, Tanios.

In: British Journal of Cancer, Vol. 113, No. 2, 14.07.2015, p. 220-225.

Research output: Contribution to journalArticle

Wu, C, Mikhail, S, Wei, L, Timmers, C, Tahiri, S, Neal, A, Walker, J, El-Dika, S, Blazer, M, Rock, J, Clark, DJ, Yang, X, Chen, JL, Liu, J, Knopp, MV & Bekaii-Saab, T 2015, 'A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers', British Journal of Cancer, vol. 113, no. 2, pp. 220-225. https://doi.org/10.1038/bjc.2015.197
Wu, C. ; Mikhail, S. ; Wei, L. ; Timmers, C. ; Tahiri, S. ; Neal, A. ; Walker, J. ; El-Dika, S. ; Blazer, M. ; Rock, J. ; Clark, D. J. ; Yang, X. ; Chen, J. L. ; Liu, J. ; Knopp, M. V. ; Bekaii-Saab, Tanios. / A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers. In: British Journal of Cancer. 2015 ; Vol. 113, No. 2. pp. 220-225.
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AU - Mikhail, S.

AU - Wei, L.

AU - Timmers, C.

AU - Tahiri, S.

AU - Neal, A.

AU - Walker, J.

AU - El-Dika, S.

AU - Blazer, M.

AU - Rock, J.

AU - Clark, D. J.

AU - Yang, X.

AU - Chen, J. L.

AU - Liu, J.

AU - Knopp, M. V.

AU - Bekaii-Saab, Tanios

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N2 - 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.

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